2-heteroarylphenyl-carbapenem antibacterial agents

ABSTRACT

Carbapenems of the formula ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by aheteroarylphenyl moiety, substituted by various substituents, asdescribed in more detail below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-heteroarylphenyl-carbapenems of the present invention are notcharacterized by a broad antibacterial spectrum such as that ofthienamycin or N-formimidoyl thienamycin. Rather, their spectrum ofactivity is largely limited to gram positive microorganisms, especiallymethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococci (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyof these difficult to control pathogens. Moreover, there is anincreasing need for agents effective against such pathogens (MRSA/MRCNS)which are at the same time safe, i.e., free from undersirable toxic sideeffects. No β-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, there is no description or suggestion of a heteroarylphenyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the surprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

U.S. Pat. No. 4,978,659 describes a particular class of compounds of theformula: ##STR5## but this limited teaching in no way suggest thetotally different compounds of the present invention, nor theirsurprisingly better anti-MRSA/MRCNS activity.

SUMMARY OF INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR6## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--; ##STR7## is a 5-or 9-membered mono- or bicyclic heteroaryl ring system wherein 1 atom isO or S, or an 8-membered bicyclic heteroaryl ring system wherein 2 atomsare O and/or S;

R^(a) is each independently selected from the group consisting ofhydrogen and the radicals set out below:

a) a trifluoromethyl group: --CF₃ ;

b) a halogen atom: --Br, --Cl, --F, or --I;

c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl is optionallymono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above)

and --SO₃ M^(b) (where M^(b) is hydrogen or an alkali metal);

d) a hydroxy group: --OH;

e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁ -C₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above or tri-substituted with --F;

f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z), where

R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)--, --S(O)₂ -- or --NR^(e) --, toform a ring (where R^(e) is hydrogen, C₁ -C₄ alkyl, and C₁ -C₄ alkylmono-substituted with R^(q) and the ring is optionally mono-substitutedwith Rq as defined above);

g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) isdefined above;

h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

i) azido: N₃

j) a formamido group: --N(R^(t))--C(O)H, where

R^(t) is H or C₁ -C₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))--C(O)C₁ -C₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

l) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))--C(O)OC₁ -C₄alkyl, where R^(t) is as defined above, and the alkyl group is alsooptionally mono-substituted by R^(q) as defined above;

m) a ureido group: --N(R^(t))--C(O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) areas defined above;

o) a cyano group: --CN;

p) a formyl or acetalized formyl radical: --C(O)H or --C(OCH₃)₂ H;

q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁ -C₄ alkyl, where the alkyl is optionally mono-substitutedby R^(q) as defined above;

r) carbonyl radical: --C(O)R^(s), where R^(s) is as defined above;

s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --C(R^(y))═NOR^(z) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

t) a (C₁ -C₄ alkoxy)carbonyl radical: --C(O)OC₁₋₄ alkyl, where the alkylis optionally mono-substituted by R^(q) as defined above;

u) a carbamoyl radical: --C(O)N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

w) a thiocarbamoyl group: --C(S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above;

x) carboxyl: --COOM^(b), where M^(b) is as defined above;

y) thiocyanate: --SCN;

z) trifluoromethylthio: --SCF₃ ;

aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

ab) an anionic function selected from the group consisting of: phosphono[P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S in the case ofa 5-membered ring, and in which from 1 to 2 additional carbon atoms areoptionally replaced by a nitrogen heteroatom, and where the phenyl andheteroaryl are optionally mono-substituted by R^(q), as defined above;M^(b) is as defined above; and R^(y) and R^(z) are as defined above;

ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in the ringis replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄ alkyl)and in which one additional carbon atom may be replaced by NH or N(C₁-C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above and phenyl which is optionally substitutedby R^(q) as defined above;

ae) C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above;

af) C₁ -C₄ alkyl radical;

ag) C₁ -C₄ alkyl mono-substituted by one of the substituents a)-ac)above;

ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from --S-- and NR^(t)(where R^(t) is as defined above) and one of the saturated carbon atomsof the oxazolidinone ring is optionally mono-substituted by one of thesubstituents a) to ag) above; and

M is selected from:

i) hydrogen;

ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group; or

iii) an alkali metal or other pharmaceutically acceptable cation.

The present invention also provides novel carbapenem intermediates ofthe formula: ##STR8## wherein: R is H or CH₃ ;

R^(a) is defined above, with the proviso that R^(q) additionallyincludes OP' where P' is defined below, that M^(a) and M^(b) of R^(q)both include M and that the Type d) hydroxy substituent additionally maybe protected hydroxy, OP';

P' is a removable protecting group for hydroxy; and

M is a removable protecting group for carboxy.

Preferred intermediates have the formula: ##STR9## wherein: R is H orCH₃ ;

P' is a removable protecting group for hydroxy;

M is a removable protecting group for carboxy;

R^(a) is selected from the group consisting of H, OP', Cl, Br, I, SCH₃,CN, CHO, SOCH₃, SO₂ CH₃, CO₂ M, CH₂ OP' or CONH₂ ; and with the provisothat the --CH₂ OH substituent is in the 3- or 4-position of theheteroaromatic ring; and

X is O or S.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthetic scheme followed by deprotection. The objective ofthe first synthetic stage is to produce a base heteroarylphenyl(hereinafter HAP) compound which may be converted to be the two-positionsubstituent of the carbapenem of Formula I. The objective of the secondsynthetic stage is to attach the base HAP to the carbapenem. Finally,the objective of the third synthetic stage is to substitute the HAP withthe desired R^(a). This third synthetic stage may either be performedafter the first synthetic stage or after the second synthetic stageaccording to the nature of the desired R^(a).

Flow Sheet A demonstrates a suggested first stage synthesis. Flow SheetsB1 and B2 demonstrate a second stage synthesis. The third stagesynthesis varies according to the selected R^(a). ##STR10##

Flow Sheet A

Substituted bromophenylboronic acids A1 and substitutedheteroaryldiethylboranes A5 may be prepared by conventional methods.Exposure of either of these boron compounds to aryl halides in thepresence of a catalytic amount of palladium catalyst yields the desiredsynthons A3.

Some of these desired synthons A3 may be prepared by the generalsynthetic routes published in the literature.

Flow Sheet B1

The second stage synthesis is to attach the base HAP to the 2-positionof the carbapenem. With compatible R^(a) or suitable precursorsubstituents therefor, HAP A3 may be added to azetidin-2-one B1 in aGrignard reaction as shown in Flow Sheet B. (B1 is subgeneric to themore general B1*. Replacing B1 by B1* (where M is as defined above underii) produces a broader class of compounds analogous to B2, B3, and B4).

The Grignard reaction requires that A3 be converted to a Grignardreagent by reaction with magnesium and 1,2-dibromoethane in THF from 20°C. to 60° C. and subsequently contacting A3 as a Grignard reagent withB1 in THF at from -70° C. to about 20° C. to produce azetidin-2-one B2.Alternatively, A3 may be reacted with t-butyllithium, n-butyllithium, orthe like in Et₂ O or THF at from -78° to -50° C. followed by theaddition of magnesium bromide to produce the same Grignard reagent.R^(i) of B1 is in practice pyridin-2-yl but may clearly be a variety ofsubstituents including aromatic and heteroaromatic substituents.Further, R^(i) might be, for example, phenyl, pyrimidinyl or thiazolyl.

Azetidin-2-one B2 is an intermediate that may be ring closed to acarbapenem. It is on this intermediate that R^(a) or precursorsubstituent such as t-butyldimethylsilyloxy-methyl group should bemodified where such modification is incompatible with the carbapenemnucleus. For example, a convenient reaction to remove thet-butyldimethylsilyl group from a hydroxymethyl substituent of the HAPon compound B2 is to expose compound B2 to a dilute solution of sulfuricacid or hydrochloric acid in methanol at 0° C. If thet-butyldimethylsilyl group were removed from carbapenem B3 under thesame conditions, a substantial portion of carbapenem would be degradedand lost. Thus, modification of the precursor substituent in thisinstance and replacement with another precursor substituent or evenR^(a) is best performed before closing the carbapenem. Of course it ispossible to remove the t-butyldimethylsilyl group from carbapenem B3 inreduced yield by exposing B3 to tetra-n-butylammonium fluoride andacetic acid in THF.

Compound B2 may be ring closed to carbapenem B3 by refluxing in xylenewith p-hydroquinone for about 1 to 2 hours. It is on this intermediatethat final elaboration of R^(a) from a precursor substituent, e.g.hydroxymethyl, may be accomplished. Removal of the protecting groupsthen provides the final compound Formula I. Such final elaboration anddeprotection is described in further detail below. ##STR11##

Flow Sheet B2

Flow Sheet B2 shows an alternative second stage synthesis, i.e.attachment of the base HAP such as B5 to the 2-position of thecarbapenem. This synthesis involves a palladium catalyzed cross-couplingreaction between a carbapenem triflate and a suitably substitutedarylstannane, a process which is described in U.S. Ser. No. 650,111filed Feb. 4, 1991. In order to apply this synthesis, it is firstnecessary to modify B5 to the trimethylstannylheteroarylphenyl B6. Thisis accomplished by reacting B5 with t-butyllithium in THF at from -78°to -50° C. followed by the addition of trimethyltin chloride.Alternatively, B6 may be prepared by simply heating B5 withhexamethylditin in the presence of tetrakistriphenylphosphine palladiumin toluene solution. At this intermediate stage, it may be desirable toremove certain protecting groups if employed on a precursor substituentR^(a). For instance, a protecting group such ast-butyldimethylsilylsilyl on a hydroxymethyl substituent may be removedby exposure to tetra-n-butylammonium fluoride in THF yielding aparticular B6. If the t-butyldimethylsilyl group were removed fromcarbapenem B7 under the same conditions, a substantial portion of thecarbapenem would be degraded and lost. Thus, modification of theprecursor substituent in this instance and replacement with anotherprecursor substituent or even an R^(a) is best performed beforeattachment to the carbapenem.

The steps for preparing the 2-oxocarbapenam intermediate B8 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Letters, 21, 2783 (1980), T. Salzmann et al., J. Am.Chem. Soc., 102, 6161 (1980), and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 108, 4675 (1986). The syntheses are alsodisclosed in U.S. Pat. Nos. 4,269,772; 4,350,631; 4,383,946; and4,414,155 all incorporated herein by reference.

Referring again to Flow Sheet B2, the 2-oxocarbapenam, B8, is reacted at-78° C. to -50° C. with a suitable trifluoromethanesulfonyl source, suchas trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chlorideand the like, in the presence of an organic nitrogen base, such astriethylamine, diisopropylamine and the like, in a polar aproticsolvent, such as tetrahydrofuran or methylene chloride. Optionally, anorganic nitrogen base, such as triethylamine and the like, is then addedto the reaction solution followed immediately by a silylating agent,such as trimethylsilyl trifluoromethanesulfonate to provide intermediateB9. An aprotic polar coordinating solvent, such as DMF,1-methyl-2-pyrrolidinone and the like, is optionally added. This isfollowed by the addition of a palladium compound, such astris(dibenzylideneacetone)dipalladium-chloroform (Pd₂ (DBA)₃.CHCl₃),palladium acetate and the like, optionally, a suitably substitutedphenylphosphine, such as tris(4-methoxyphenyl)phosphine,tris(2,4,6-trimethoxyphenyl)phosphine and the like, and the stannane B6.A halide source such as lithium chloride, zinc chloride or ammoniumchloride and the like, is added and the reaction solution is allowed towarm and is stirred at a suitable temperature, such as 0° to 50° C. forfrom a few minutes to 48 hours. The carbapenem B7 is obtained byconventional isolation/purification methodology known in the art.

Generally speaking, the milder conditions of the synthesis shown in FlowSheet B2 allow for a wider range of functional group R^(a) to be presentthan the synthesis illustrated in Flow Sheet B1. However, in certaincases, it is advantageous for the R^(a) substituent(s) of the stannaneB6 to be introduced in a protected or precursory form. Final elaborationof R^(a) from a precursor substituent, e.g. hydroxymethyl, may beaccomplished on carbapenem intermediate B7. Removal of hydroxyl andester protecting groups then provides the final compound, C5 of FormulaI. Such final elaboration and deprotection is described in detail below.##STR12##

Flow Sheet C

Azetidin-2-ones B1 and B1* (Flow Sheet B1), pyridyl-thioesters, are wellknown compounds in the production of carbapenems. Diverse syntheticschemes useful to make B1 and B1* may be imagined by the skilledartisan. Particularly useful to the instant inventors is a syntheticscheme set out further in Flow Sheet C below in which the symbol R is asdefined above. The steps for preparing intermediate B1 and B1* areanalogous to the procedures described, for example, in U.S. Pat. Nos.4,260,627 and 4,543,257; L. D. Cama et al. Tetrahedron 39, 2531 (1983);R. N. Guthikonda et al. J. Med. Chem., 30, 871 (1987) herebyincorporated by reference, as discussed below. ##STR13##

The general synthesis description depicted above in the Flow Sheetsshows a protected 1-hydroxyethyl substitution on the 6-position of thecarbapenem. After final deprotection, a 1-hydroxyethyl substituent isobtained, which is preferred in most cases. However, it has been foundthat with certain 2-side-chain selections, the ultimate balance offavorable properties in the overall molecule may be enhanced byselection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23(8), 1915 (1985); BE 900 718 A(Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).

In the compounds of the present invention, the R^(a) substituents can beselected based on the biological properties which they confer. Inrelated compounds, it has been found that the neutral or anionicsubstituted compounds afford greater water solubility and reducedpotential for CNS side effects. Substituents which tend to conferimproved water solubility on the overall compound have been founduseful, since they are contemplated to thereby improve the transport ofthe compound involved. Although a substantial number and range ofsubstituents have been described herein, all of these are contemplatedto be a part of the present invention based on the biologicalperformance of substituents related in terms of their medicinalchemistry. ##STR14## is a 5-, 8-, or 9-membered mono- or bicyclicaromatic ring system wherein up to two carbon atoms are replaced by O orS. HAR can be represented by ##STR15## (where Ax is phenylene or abivalent 5-membered aromatic ring wherein one carbon atom is replaced byO or S).

Thus, this aryl structure may be the radical of a 5-membered furan orthiophene, of an 8-membered furofuran, thienofuran, or thienothiophene,or of a 9-membered benzofuran or benzothiophene. The carbon atom at thepoint of attachment, however, cannot be replaced by a heteroatom.

The R^(a) substituents are on the carbon atoms of the aryl ring systembut not on the one at the point of attachment. It is preferred thatR^(a) =H when it is α to the point of attachment.

In preferred compounds of Formula I, R¹ is hydrogen. More preferably, R¹is hydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--. In the mostpreferred case, R¹ is H and R² is (R)--CH₃ CH(OH). While R═H is usuallypreferred, there are instances in which R═CH₃ may provide improvedchemical stability, water solubility, or pharmacokinetic behavior. Thesubstituent R═CH₃ may be of either configuration, i.e., the α orβ-stereoisomer. Additionally, in preferred compounds, at least one R^(a)in the meta-position of the HAP moiety from the point of attachment tothe other aromatic ring is other than hydrogen. In the most preferredcompounds, in total, up to two R^(a) substituents are other thanhydrogen.

Among preferred R^(a) substituents are C₁ -C₄ alkyl mono-substitutedwith hydroxy, such as, hydroxymethyl; formyl; carbamoyl, such as,--CONH₂ ; hydroxyiminomethyl, such as, --CH═NOH; cyano; or halogen suchas chloro, bromo, and iodo.

Flow Sheet D

In regard to this preferred substitution, the hydroxymethyl group may beobtained in the R^(a) position of the phenyl portion of HAP as shown inFlow Sheet D, in which A3 is obtained as given in Flow Sheet A.Selective metallation of A3 and formylation with N,N-dimethylformamideprovides synthon D1. Reduction of D1 with sodium borohydride in methanolyields the preferred substituent which is protected as its silylether inthe next step to give D3. The latter reagent is then incorporated intoFlow Sheet B1 as A3. The preferred hydroxymethyl group may also beobtained in the appropriate R^(a) positions of the heteroaryl portion ofHAP. Thus, by a judicious choice of starting materials as exhibited inFlow Sheet A, the desired substitution pattern is readily available.##STR16##

The preferred formyl substitution on the HAP moiety may be obtained fromthe hydroxymethyl substitution of B3 or isomeric B3* described in FlowSheet B1 by a Swern oxidation. For example, isomeric B3 is oxidized inmethylene chloride at from -70° C. to room temperature employing oxalylchloride-dimethyl sulfoxide as the active agent. Obviously, the positionof the resultant formyl substitution will depend upon the position ofthe hydroxymethyl substitution in isomeric B3.

The preferred --CH═NOH substitution on the HAP moiety may beconveniently obtained from the formyl substitution just described. Thisis accomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the HAP moiety may be obtained fromthe --CH═NOH substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The preferred carbamoyl substitution, --CONH₂, may be obtained from B2or "isomeric" B2 by oxidizing hydroxymethyl with Jones reagent to thecorresponding carboxylic acid substitution as described above. Thiscarboxylic acid is converted to --CONH₂ by sequentially contacting with1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride,1-hydroxy-benzotriazole, and ammonia in an organic solvent at roomtemperature. Substituted amides may of course be obtained by replacingammonia with the corresponding substituted amine. In contrast to thecarboxylic acid substitution, this carbamoyl substituent requires noprotection from the conditions of carbapenem cyclization. Deprotectionfollowing cyclization is carried out with palladium catalyzeddeallylation in a solution containing potassium or sodium2-ethyl-hexanoate as described in McCombie and Jeffrey, J. Org. Chem.,47, 2505 (1983). Deprotection in such a solution yields the desiredpotassium or sodium salt.

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the final product is prepared.Suitable hydroxyl protecting groups, P', are silyl groups such astrialkylsilyl, aryl(alkyl)alkoxysilyl, alkoxydiarylsilyl anddiarylalkylsilyl and carbonate groups such as alkyloxycarbonyl,substituted alkyloxycarbonyl, benzyloxycarbonyl, substitutedbenzyloxycarbonyl, allyloxycarbonyl and substituted allyloxycarbonyl.The preferred protecting groups, in addition to or including those shownin the schemes, are t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl andallyloxycarbonyl. Suitable carboxyl protecting groups, M, in addition toor including those shown in the schemes are described herein below.

Deblocking may be carried out in a conventional manner, with care beingtaken to avoid a procedure which is so harsh as to disrupt otherportions of the final product molecule. For compounds prepared accordingto Flow Sheet B1, deprotection may be carried out in a palladiumcatalyzed reaction in a solution containing potassium 2-ethylhexanoateand 2-ethylhexanoic acid or, alternatively, another suitable nucleophilesuch as pyrrolidine. Alternatively, for those prepared via Flow SheetB2, deprotection is conducted sequentially. Thus, compound B7 is exposedinitially to aqueous acidic conditions, acetic acid or dilute HCl or thelike, in an organic solvent such as tetrahydrofuran at 0° C. to ambienttemperature for from a few minutes to several hours. The resultingdesilylated carbapenem may be isolated by conventional techniques, butis more conveniently taken into the final deprotection process. Thus,addition of an inorganic base such as NaHCO₃ or KHCO₃ and a catalyst,such as, 10% Pd/C or 5% Rh/Al₂ O₃ followed by hydrogenation provides forthe removal of the p-nitrobenzyl protecting group and the formation ofthe final compound of Formula I.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(x)group, to have a specific and limited meaning, being only monocyclic. Itis required that the monocyclic heteroaryl have at least one nitrogenatom, and optionally at most only one additional oxygen or sulfurheteroatom may be present. Heteroaryls of this type are pyrrole andpyridine (1N); and oxazole, thiazole or oxazine (1N+1 O or 1 S). Whileadditional nitrogen atoms may be present together with the firstnitrogen and oxygen or sulfur, giving, e.g., a thiadiazole (2N's+1S),the preferred heterozryls are those where only nitrogen heteroatoms arepresent when there is more than one. Typical of these are pyrazole,imidazole, pyrimidine and pyrazine (2N's) and triazine (3N's).

The heteroaryl group of R^(x) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstitutent choices may not be appropriate.

Listed in Table I are specific compounds of the instant invention. Inthe table, R² substituents containing a chiral center (i.e., --CH(F)CH₃and --CH(OH)CH₃) have the (R) configuration, and the R^(a) column refersto the substituent on the phenyl ring.

                                      TABLE I                                     __________________________________________________________________________                                       I'                                          ##STR17##                                                                    No.                                                                              R   R.sup.2 M R.sup.a                                                                             HARR.sub.2.sup.a                                       __________________________________________________________________________    1  H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR18##                                             2  H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR19##                                             3  H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR20##                                             4  H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR21##                                             5  H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR22##                                             6  H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR23##                                             7  H   CH(OH)CH.sub. 3                                                                       Na                                                                              I                                                                                    ##STR24##                                             8  H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR25##                                             9  H   CH(OH)CH.sub.3                                                                        Na                                                                              SMe                                                                                  ##STR26##                                             10 H   CH(OH)CH.sub.3                                                                        Na                                                                              SMe                                                                                  ##STR27##                                             11 H   CH(OH)CH.sub.3                                                                        Na                                                                              S(O)Me                                                                               ##STR28##                                             12 H   CH(OH)CH.sub.3                                                                        Na                                                                              S(O)Me                                                                               ##STR29##                                             13 H   CH(OH)CH.sub.3                                                                        Na                                                                              SO.sub.2 Me                                                                          ##STR30##                                             14 H   CH(OH)CH.sub.3                                                                        Na                                                                              SO.sub.2 Me                                                                          ##STR31##                                             15 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR32##                                             16 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR33##                                             17 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR34##                                             18 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR35##                                             19 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR36##                                             20 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR37##                                             21 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR38##                                             22 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR39##                                             23 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR40##                                             24 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR41##                                             25 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR42##                                             26 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR43##                                             27 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR44##                                             28 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR45##                                             29 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR46##                                             30 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR47##                                             31 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHNOH                                                                                ##STR48##                                             32 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHNOH                                                                                ##STR49##                                             33 H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR50##                                             34 H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR51##                                             35 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR52##                                             36 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR53##                                             37 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR54##                                             38 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR55##                                             39 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR56##                                             40 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR57##                                             41 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR58##                                             42 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR59##                                             43 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR60##                                             44 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR61##                                             45 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR62##                                             46 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR63##                                             47 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR64##                                             48 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR65##                                             49 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR66##                                             50 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR67##                                             51 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR68##                                             52 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR69##                                             53 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR70##                                             54 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR71##                                             55 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR72##                                             56 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR73##                                             57 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR74##                                             58 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR75##                                             59 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR76##                                             60 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR77##                                             61 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR78##                                             62 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR79##                                             63 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR80##                                             64 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR81##                                             65 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR82##                                             66 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR83##                                             67 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR84##                                             68 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR85##                                             69 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR86##                                             70 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR87##                                             71 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR88##                                             72 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR89##                                             73 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR90##                                             74 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR91##                                             75 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR92##                                             76 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR93##                                             77 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub. 2 OH                                                                         ##STR94##                                             78 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR95##                                             79 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR96##                                             80 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR97##                                             81 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR98##                                             82 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR99##                                             83 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR100##                                            84 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR101##                                            85 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR102##                                            86 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR103##                                            87 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR104##                                            88 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR105##                                            89 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR106##                                            90 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR107##                                            91 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR108##                                            92 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR109##                                            93 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR110##                                            94 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR111##                                            95 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR112##                                            96 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR113##                                            97 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR114##                                            98 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR115##                                            99 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR116##                                            100                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR117##                                            101                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR118##                                            102                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR119##                                            103                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR120##                                            104                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR121##                                            105                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR122##                                            106                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR123##                                            107                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR124##                                            108                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR125##                                            109                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR126##                                            110                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR127##                                            111                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR128##                                            112                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR129##                                            113                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR130##                                            114                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR131##                                            115                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR132##                                            116                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR133##                                            117                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR134##                                            118                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR135##                                            119                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR136##                                            120                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR137##                                            121                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR138##                                            122                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR139##                                            123                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR140##                                            124                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR141##                                            125                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR142##                                            126                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR143##                                            127                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR144##                                            128                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR145##                                            129                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR146##                                            130                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR147##                                            131                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR148##                                            132                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR149##                                            133                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR150##                                            134                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR151##                                            135                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR152##                                            136                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR153##                                            137                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR154##                                            138                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR155##                                            139                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR156##                                            140                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR157##                                            141                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR158##                                            142                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR159##                                            143                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR160##                                            144                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR161##                                            145                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR162##                                            146                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR163##                                            147                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR164##                                            148                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR165##                                            149                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR166##                                            150                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR167##                                            151                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR168##                                            152                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR169##                                            153                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR170##                                            154                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR171##                                            155                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR172##                                            156                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR173##                                            157                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR174##                                            158                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR175##                                            159                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR176##                                            160                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR177##                                            161                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR178##                                            162                                                                              H   CH(F)CH.sub.3                                                                         Na                                                                              H                                                                                    ##STR179##                                            163                                                                              H   CH(F)CH.sub.3                                                                         Na                                                                              H                                                                                    ##STR180##                                            164                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR181##                                            165                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR182##                                            166                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR183##                                            167                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR184##                                            168                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR185##                                            169                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR186##                                            170                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR187##                                            171                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR188##                                            172                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR189##                                            173                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR190##                                            174                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR191##                                            175                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR192##                                            176                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR193##                                            177                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR194##                                            178                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR195##                                            179                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR196##                                            180                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR197##                                            181                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR198##                                            182                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR199##                                            183                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR200##                                            184                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR201##                                            185                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR202##                                                                          ##STR203##                                            186                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR204##                                                                          ##STR205##                                            187                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR206##                                            188                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR207##                                            189                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR208##                                            190                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR209##                                            191                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR210##                                                                          ##STR211##                                            192                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR212##                                                                          ##STR213##                                            193                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR214##                                            194                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR215##                                            195                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR216##                                            196                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR217##                                            197                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR218##                                            198                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR219##                                            199                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR220##                                            200                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR221##                                            201                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR222##                                            __________________________________________________________________________

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above may also includenon-toxic acid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

The pharmaceutical acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogenation. Broadly, such ester protectinggroups include alkyl, substituted alkyl, benzyl, substituted benzyl,aryl, substituted aryl, allyl, substituted allyl and triorganosilyl.Examples of specific such ester protecting groups include benzhydryl,p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, t-butyl,2,2,2-trichloroethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,trimethylsilyl, 2-(trimethyl)silylethyl, phenacyl, p-methoxybenzyl,acetonyl, o-nitrobenzyl and 4-pyridylmethyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of a DHP inhibitor. However, such use isoptional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenem antibacterial agents aredisclosed in the prior art [see European Patent Applications No.79102616.4 filed Jul. 24, 1979 (Patent No. 0 007 614); and No.82107174.3, filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1.) define the procedure for determining DHP susceptibilityof the present carbapenems and 2.) disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting.

All temperatures are in degrees Celsius.

STARTING MATERIAL SYNTHESES ##STR223## 3-BROMOPHENYLBORONIC ACID

N-Butyllithium (2.5M; 44 mL; 0.11M) was added dropwise over 15 mins. toa vigorously stirred solution of m-dibromobenzene (25 g; 0.106M) in 500mL of anhydrous ether at -78° under nitrogen. After stirring 10 mins.more, a solution of triisopropylborate (25.3 mL; 0.11M) in anhydrousether (200 mL) was added over 20 mins. The cooling bath was thenremoved, and the stirring solution was allowed to warm to R.T. over ˜2hrs. A small amount of solid separated. After stirring 15 mins. more atR.T., 150 mL of ice cold 8% aqueous hydrochloric acid was cautiouslyadded, and the stirring was continued for 15 mins. The organic phase wasseparated, washed with 2×100 mL of saturated sodium chloride solution,and dried over anhydrous magnesium sulfate. Solvent removal gave ˜30 Gof crude product as a semi-solid, which was shaken well with 150 mL ofhexane. The solid was filtered and washed with 2×25 mL of hexane. Theresulting silky solid (mp 178°-9° C. after softening at ˜ 160° C.) (6.5g) was used as 3-bromophenylboronic acid with a small amount ofcontamination. The hexane filtrate was concentrated and the residue wasstirred well with 150 mL of petroleum ether (30°-60°). The resultingsolid was filtered and washed with 2×25 mL of petroleum ether. Thisresulting solid (4.4 g) melting at 178.3°-179° C. was the desired3-bromophenylboronic acid.

NMR: 7.38-7.46; 7.70-7.80; 8.1-8.18; 8.31 (aromatic H's) ##STR224##

2-(3'-BROMOPHENYL)THIOPHENE

To stirred solution of m-bromoaniline (34.4 g; 0.2M) in thiophene (200mL) was added isoamylnitrite (46.86 g; 0.4M) dropwise over a period of30 mins. at 0° C. The resulting mixture was cautiously warmed to R.T.and heated to reflux for 16 hours. The reaction mixture was cooled,diluted with 400 mL of ether, washed with 3×100 mL of satd. sodiumchloride solution, and dried over anhydrous magnesium sulfate. Solventand excess thiophene were removed. A solution of the residue in 200 mLof ether was filtered through 50 G silica gel bed. Solvent was removed,and the residue was distilled to give 34% of 2-(3'-bromophenyl)thiopheneas a yellow liquid boiling at 130°-2°/˜0.2 mm. This liquid solidified onstanding in the refrigerator.

NMR: 7.06-7.78 ##STR225##

2-(4'-BROMOPHENYL)THIOPHENE

Similarly, 2-(4'bromophenyl)thiophene was prepared from 4-bromo anilinein 29% yield as a yellow oil boiling at 146°-8°/˜0.5 mm.

NMR: (C₆ D₆): 6.68-6.92 (thiophene H's) 7.03-7.20 (p-phenyl H's).

2-PHENYLTHIOPHENE

The above method was used to prepare 2-phenylthiophene from aniline in11% yield as colorless liquid boiling at 110°-113°/˜3 mm. ##STR226##

3-(3'-BROMOPHENYL)THIOPHENE

The thiophene was prepared according to G. Martelli et al., J. Chem. Soc(B)., 901, (1968). ##STR227##

2-(3',5'-DIBROMOPHENYL)THIOPHENE

3,5-dibromoaniline, upon similar treatment, gave2-(3',5'-dibromophenyl)thiophene in 55% yield as a yellow oil, whichsolidified as a glassy solid.

NMR: 7.04-7.68 (aromatic H's) ##STR228##

2-FORMYL-5-(3'-BROMOPHENYL)THIOPHENE

Phosphorus oxychloride (1.15 mL; 15.4 mM) was added slowly to stirringdimethylformamide (0.95 mL; 12.2 mM) at -10° under nitrogen. Theresulting mixture was stirred for 15 mins. 2-(3'-bromophenyl)thiophene(2.12 g; 9 mM) was then added. The reaction mixture was then warmedslowly to 110° over a period of 1 hr. cooled and poured into ice, andcautiously neutralized with sodium carbonate. Extraction with ethylacetate and drying the organic phase with anhydrous magnesium sulfateprovided upon concentration 2.16 g of the desired aldehyde as an oilysolid.

NMR: 7.26-7.84 (aromatic H's); 9.92(--C(O)H; S) ##STR229##

2-(HYDROXYMETHYL)-5-(3'-BROMOPHENYL)THIOPHENE

Sodium borohydride (400 mg; 10 mM) was added portionwise over 5 min. toa stirred suspension of the above crude aldehyde (2.16 g) in 100 mL ofmethanol at 0° C. The resulting clear solution was stirred 30 mins.Solvent was then removed in vacuo at R.T. The residue was taken up in 50mL of ethyl acetate, washed with 3×20 mL of sat'd. sodium chloridesolution, and dried over anhyd. magnesium sulfate. Solvent removalfollowed by silica gel chromatography with methylene chloride gave 1.355g of desired alcohol as an amorphous solid. NMR: 1.83 (OH; t; J-6H3);4.82(CH₂ ; d; J-6H₃); 6.96-7.75 (aromatic H's) ##STR230##

2-(t-BUTYLDIMETHYLSILYLOXYMETHYL)-5-(3'-BROMOPHENYL)THIOPHENE

To a stirred solution of 2-(hydroxymethyl)-5-(3'-bromophenyl)thiophene(1.08 G; 4 mM) and triethylamine (1.4 mL; 10 mM) in 20 ml of methylenechloride at R.T. was added t-butyldimethylchlorosilane (1.5 g; 10 mM).This mixture was stirred overnight, diluted with 30 ml of ethyl acetate,washed with 2×15 ml of sat'd. sodium chloride solution, and dried overanhyd. magnesium sulfate. Solvent was removed to give a residue, whichwas purified on silica gel with ether: petroleum ether (1:20) as solventmixture. Eluate was distilled to give 0.99 g of2-(t-butyldimethylsilyloxymethyl)-5-(3'bromophenyl)thiophene ascolorless liquid boiling at 167°-170°/˜0.2 mm.

NMR: 0.17 & 0.95 (silyl methyls); 4.88 (s, CH₂); 6.88-7.75 (aromaticH's) ##STR231##

2-[3'-BROMO-5'-METHYLTHIO)PHENYL]THIOPHENE

2.5M n-Butyllithium (1.5 mL; 3.75 mM) was added dropwise to a solutionof 2-(3',5'-dibromophenyl)thiophene (1.06 g; 3.33 mM) in anhydroustetrahydrofuran (7 mL) at -78° under nitrogen. The reaction mixture wasthen stirred 10 min. and a solution of dimethyldisulfide (0.9 mL; 10 mM)in 3 mL of anhydrous tetrahydrofuran was added. The resulting mixturewas stirred overnight at R.T. after which 5 mL of sat'd. ammoniumchloride and 20 mL of ethyl acetate were added. The organic phase wasseparated, washed with 2×10 mL of sat'd. sodium chloride solution, anddried over anhyd. magnesium sulfate. Solvent removal, and purificationon silica gel using hexane as solvent gave a liquid, which was distilledto give 52% of 2-[(3'-bromo)-(5'-methylthio)]phenylthiophene as acolorless oil boiling at ˜150°-152°/˜0.2 mm. (oil bath temp. 180°)

NMR: 1.52(SCH₃ ; s); 7.00-7.50 (aromatic H's) ##STR232##

2-BROMO-5-[3'-BROMOPHENYL]THIOPHENE

A solution of bromine (8 g; 50 mM) in 20 mL of glacial acetic acid wasadded dropwise to a vigorously stirred solution of2-(3'-bromophenylthiophene (12 g; 50 mM) in 80 mL of glacial aceticacid. The resulting mixture was heated to reflux 5 hrs, cooled andpoured onto ice. A solid separated which was filtered and washed withice water, and purified on silica gel using hexane as solvent to give68% of 2-bromo-5-[3'-bromophenyl]thiophene as an amorphous solid.

NMR: 7.00-7.68 (aromatic H's)

3-(3'-BROMOPHENYL)-5-BROMOTHIOPHENE ##STR233##

To a solution of 3-(3'-bromophenyl)thiophene, (G. Martelli et al., J.Chem. Soc., (B), 901, 1968) (712 mg, 3 mmol) in acetic acid (6.2 ml)with stirring under N₂, a solution of Br₂ (154 μl, 3 mmol) in aceticacid (4.8 ml) was added dropwise. The resultant orange-red solution washeated for 5 hours at 100° C. After cooling, the reaction mixture waspoured into ice water with stirring. A non-filterable milky precipitatewas extracted 2× with Et₂ O. The combined Et₂ O layers were carefullyextracted 3× with NaHCO₃ solution and then 2× with brine. After drying(MgSO₄), filtering and concentrating, the residue was chromatographed ona column of Bakers Si Gel (60-200 mesh) packed, applied and eluted withhexane. Those fractions containing the slightly less polar product werecombined and concentrated in vacuo (763 mg). Preparative TLC of 663 mgof this material on 7-1000μ Si Gel GF plates (eluting with hexane andextracting with CH₂ Cl₂) provided a purer sample of the desired 5-bromoisomer (416 mg) (i.e., less of the undesired 2-bromo isomer waspresent). Approximately 162 mg of this material was further purified bypreparative TLC on 4-1000μ Si Gel GF (eluting and extracting as above)to give 3-(3'-bromophenyl)-5-bromothiophene pure enough for furtherreaction (196 mg).

MS: m/z 316/318/320 (MI).

¹ H NMR (300 MHz, CDCl₃)): δ7.01 (d, J=6 Hz, H₄ of 2-Br compound);7.23-7.70 (series of m's, phenyl and thiophene protons of the minor 2-Brand the desired 5-Br isomers). ##STR234##

2-METHYLTHIO-5-[3'-BROMOPHENYL]THIOPHENE

A2.5M solution of n-butyllithium (2.2 mL; 5.5. mM) was slowly added to asolution of 2-bromo-5(3'-bromophenyl)thiophene (1.59 g; 5 mM) in 10 mLof tetrahydrofuran at -78° under nitrogen. The mixture was stirred 10mins. and dimethyldisulfide (1.35 mL; 15 mM) was added slowly. Thismixture was stirred overnight at R.T. after which 5 mL of sat'd.ammonium chloride and 15 mL of ethyl acetate were added. The organicphase was separated, washed with 2×5 mL of sat'd. sodium chloride, anddried over anhyd. magnesium sulfate. Solvent removal and purification onsilica gel with hexane as solvent gave2-methylthio-5-(3'-bromophenyl)thiophene as a colorless oil boiling at142°-5°/0.5 mm.

NMR: 2.54 (SCH₃ ; s); 7.02-7.72 (aromatic H's)

3-(3'-BROMOPHENYL)-5-THIOPHENE CARBOXALDEHYDE ##STR235##

To a solution of the brominated thiophene (mainly the correct 5-bromoisomer; 196 mg, 0.62 mmol) in ether (2.7 ml) at -78° C. under N₂, 1.6MBuLi in hexane (388 μl, 0.62 mmol) was added dropwise. After 15 min. at-78° , DMF (63 μl, 0.81 mmol) was added, and the reaction mixture wasstirred overnight at ambient temperature. The reaction was partitionedbetween EA and brine. After phase separation, the organic layer wasagain extracted with brine, dried, filtered and concentrated to providecrude formylated product (151 mg). Preparative TLC on 3-1000μ Si Gel GFplates (eluting with 20% Et₂ O/hexane and extracting with CH₂ Cl₂)provided a major band containing a mixture (80 mg) of the desired5-formyl isomer contaiminated with a small amount of the 2-formylisomer.

MS: m/z 266/268 (MI.)

IR(CH₂ Cl₂): 1670 (formyl) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): δ 7.22 (low amplitude d, J=5 Hz, H₄ of minoramount of 2-formyl); 7.29-8.00, (series of m's phenyl & thiopheneprotons); 9.88 (d, J=1 Hz, long range splitting minor amount of,2-formyl); 9.98 (d, J=1 Hz, CHO of 5-formyl, allylic splitting).

3-[(3'-BROMOPHENYL)-(5-HYDROXYMETHYL)]THIOPHENE ##STR236##

To a solution of the formylated thiophene (79 mg, 0.3 mmol) stirred inMeOH (3 ml) at 0°, NaBH₄ (13.6 mg, 0.34 mmol) was added, and stirringwas continued for 40 min. Upon concentration to an oil under a N₂stream, the residue was partitioned between EA and brine, the organiclayer was again washed with brine, dried, filtered and concentrated invacuo to give the crude product (77 mg). Preparative TLC on 2-1000μ SiGF plates (eluting with CH₂ Cl₂ and extracting the major UV band with10% MeOH/CH₂ Cl₂) provided the purified 5-hydroxymethyl compound (70 mg.88% yield). A small amount of faster running material (5 mg, 6% yield)proved to be the undesired 2-hydroxymethylthiopen compound having thewidely split H4-doublet (J=4.5 Hz). The desired product contained noneof this impurity.

MS: m/z 268/250(MI)

IR(CHCl₂): 3600(OH) cm⁻¹

¹ H NMR (300 MHz, CDC13): δ 1.84 (t, J=6 Hz, OH); 4.85(dd, J=0.5(allylic coupling to H₄) and 6 Hz; CH₂ OH); 7.24, 7.42, 750 and 7.70 (4sets of m's; phenyl and thiophene H's).

NMR data for the less polar 2-hydroxymethylthiophene (5 mg above):

¹ H NMR (300 mHz, CDCl₃): δ 1.81 (t, J=6 Hz, OH); 4.82 (d, J=6 Hz, CH₂OH); 4.86 (br d, J=6 Hz, CH₂ OH of small amount of 5-isomer); 7.08 (d,J=5 Hz, H₄); 7.25-7.71 (series of multiplets, phenyl and thiopheneprotons).

3-(3'-BROMOPHENYL)-5-(t-BUTYLDIMETHYLSILYLOXYMETHYL) THIOPHENE:##STR237##

To a solution of the 5-hydroxymethyl thiophene (62 mg, 0.23 mmol) in CH₂Cl₂ (1.1 ml) at 0° C. with stirring under N₂, TBDMSiCl (183 mg, 0.55mmol) and Et₃ N (80 μl, 0.59 mmol) were added. The cooling bath wasremoved, and the reaction mixture was stirred overnight at ambienttemperature. Work-up of an aliquot showed incomplete conversion.Therefore, DMF (20 μl) in CH₂ Cl₂ (1 ml) was added, and stirring wasresumed for a few hours*. Brine containing 1M K₂ HPO₄ (1 ml) andadditional CH₂ Cl₂ were added to the reaction mixture with stirring.After phase separation, the aqueous layer was again extracted with CH₂Cl₂, and the combined organic layers were washed with brine, dried,filtered and concentrated in vacuo to give the crude product (97 mg).Preparative TLC on 2-1000μ Si Gel GF plates (eluting with 20% Et₂O/hexane and extracting with CH₂ Cl₂) provided the purified5-silyloxymethyl thiophene (79 mg, 90% yield).

MS: m/z 325/327 (MI - t-butyl); 251/253 (MI - OTBDMSi).

¹ H NMR (300 MHz, CDCl₃): δ 0.13 (s, Si(CH₃)₂); 0.94 (s, t-butyl-Si);4.89 (s, CH₂ OTBDMSi); 7.16-7.70 (series of m's, phenyl and thienylH's). ##STR238##

2-(3'-BROMOPHENYL)FURAN:

BP: 98°-105°/0.1 mm

Reference: E. L. Plummer, J. Agric. Food Chem., 31, 718-721 (1983).##STR239##

2-(t-BUTYLDIMETHYLSILYLOXYMETHYL)FURAN

To a stirring mixture of 2-furan methanol (33 g, ˜0.335M) andtriethylamine (47 mL, ˜0.335M) in anhydrous methylene chloride (200 mL)under nitrogen was added t-butyldimethylchlorosilane portionwise at roomtemperature. 20 mL of N,N-dimethylformamide was added. The resultingmixture was stirred 3 hrs. After dilution with 400 mL of ether, thereaction mixture was washed with 3×100 mL of ice-water, 100 mL ofsaturated sodium chloride solution, and dried over anhydrous magnesiumsulfate. Solvent removal gave a crude product, which was distilled toafford 39.8 g of the desired silyl ether as a colorless liquid boilingat 76°-7°/˜0.5 mm. ##STR240##

2-(3'-BROMOPHENYL)-5-(t-BUTYLDIMETHYLSILYLOXYMETHYL)FURAN

To a stirred solution of m-bromoaniline (6.88 g; 0.04M) in 42.2 g (0.2M)of 2-(t-butyldimethylsilyloxymethyl)furan at 0° was added isoamylnitrite(10.75 mL: 0.08M) dropwise over a period of 0.5 hr. The resultingmixture was then heated 16 hours at 50° C. The reaction mixture wascooled and diluted with 150 mL of ether and washed with 2×100 mL of icecold water. The organic phase was dried over anhydrous magnesiumsulfate, and the residue was distilled after filtering through 50 G ofsilica gel bed, to give 26% of the desired2-(3'-bromophenyl)-5-(t-butyldimethylsilyloxymethyl)furan as a colorlessliquid boiling at 163°-7°/˜0.5 mm.

STEP A: GENERAL SYNTHESIS OF ARYLKETONES ##STR241## METHOD 1

Aryl bromide (1 mM) was added to a stirred suspension of magnesium chips(1.25 mM) in 2 mL of anhydrous tetrahydrofuran under nitrogen at R.T. 8μL of 1,2-dibromoethane was then added. The resulting mixture wasstirred 3 hours, when most of the metal was digested. The resulting darkyellow solution was used as 0.5M solution of the aryl Grignard reagent.

This Grignard reagent solution was added dropwise to a stirred solutionof (3S,4R)-1-[[(allyloxy)carbonyl](triphenylphosphoranylidene)methyl]-3-[(1R)-1-[(allyloxy)carbonyloxy]ethyl]-4-[[2'-pyridylthio)carbonyl]methyl]azetidin-2-one,(˜0.5 mM) in 2 mL of anhydrous tetrahydrofuran at 0° under nitrogen. Thereaction mixture was stirred 15 mins at 0°. Satd ammonium chloridesolution (5 mL) and 10 mL of ethyl acetate were added. The organic layerwas separated, and washed with 2×5 mL of satd sodium chloride solutionand dried over anhyd. magnesium sulfate. Solvent removal followed bysilica gel chromatography using mixtures (1:1 to 2:1) of ethylacetate:hexane as eluant gave the desired ylid arylketone as a paleyellow foam.

METHOD 2 ##STR242##

To a stirred solution of 3 mM aryl bromide in anhydrous ether (12 mL) at-78° under nitrogen was added n-butyllithium (2.5 molar solution; 1.32mL; 3.3 mM) dropwise. The resulting mixture was stirred 0.5 hr. Asolution of magnesium bromide, freshly prepared by stirring 6.6 mM ofmagnesium turnings in 24 mL of anhydrous tetrahydrofuran with 6 mM of1,2-dibromoethane for about 1 hr under nitrogen at ambient temperature,was then added dropwise to the above stirring lithium salt at -78°. Theresulting mixture was stirred 15 mins at -78°, and 30 mins at 0°. Thethus obtained turbid solution was used as a 0.0833 molar solution of therequired aryl magnesium bromide.

This solution of the Grignard reagent was added slowly to a stirredsolution of 1.4 mM of (3S,4R)-1-[[allyloxy)carbonyl](triphenylphosphoranylidene)methyl]-3-[(1R)-1-[(allyloxy)carbonyloxy]ethyl]-2-[[(2'-pyridylthio)carbonyl]methyl]azetidin-2-one,in 5 mL of anhydrous tetrahydrofuran at 0° under nitrogen. The reactionmixture was stirred 15 mins. at 0°, and satd. ammonium chloride (15 mL)and 30 mL of ethyl acetate were added. The organic layer was separated,washed with 2×15 mL of sat'd. sodium chloride solution, and dried overanhydrous magnesium sulfate. Solvent removal and purification on silicagel using a (1:1 to 2:1) mixture of ethyl acetate:hexane gave thedesired aryl ketone, as a light yellow foam.

STEP B: GENERAL PROCEDURE FOR CYCLIZATION ##STR243##

A solution of the ylid ketone (0.25 mM) in 2 mL of p-xylene containing atiny crystal of hydroquinone was heated 45 mins. to 3 hours (dependingon the nature of R) at 130° C. under nitrogen. The solution was cooled,applied in a suitable solvent to a silica gel column packed with hexaneand then eluted first with hexane and then with 4:1 to 2:3 mixtures ofhexane:ethyl acetate to give the desired carbapenem analogs.

STEP C: GENERAL PROCEDURE FOR DEALLYLATION ##STR244##

To a stirred solution of the carbapenem (0.2 mM) in 3 mL of a 1:1mixture of methylene chloride:ether in a centrifuge tube at 0° undernitrogen were added 2-ethylhexanoic acid (0.2 mM), triphenylphosphine(0.05 mM), tetrakis-(triphenylphosphine)palladium (0.04 mM), and 0.2 mMof sodium or potassium 2-ethylhexanoate. This mixture was stirred 2 hrswhen a solid precipitated out. After diluting with 10 mL of ether, themixture was centrifuged and the supernatant liquid was decanted. Theremaining solid was stirred with 2 mL of ethyl acetate and centrifuged.The resulting solid was dissolved in 1 mL of water and applied to a1000μ reverse phase silica gel plate. Elution with mixtures ofacetonitrile:water or EtOH:water gave an ultraviolet active area, whichwas scraped and stirred with 5 mL of 4:1 acetonitrile:water mixture. Thesolid was filtered and washed with 3×2 mL of a 4:1 acetonitrile:watermixture. The filtrate was washed with 4×10 mL of hexane, concentrated to1 mL in vacuo at R.T. and lyophilized to give the sodium or potassiumsalt of the carbapenem as a white to creamy, fluffy mass.

In the following examples:

the IR data are in cm⁻¹ ;

the UV data are in nanometers for λ_(max) water; and

the NMR spectra are measured in CDCl₃ solvent unless otherwisespecified.

EXAMPLE 1 Step A ##STR245##

Conditions

A: 1) ˜1 hr.; R.T.; Mg/THF 2) 0°; 15 min; THF; pyridylthioester

Yield: 54%

Step B

Conditions: Xylene; 135°; 1.5 hrs.

Yield: 79%

Spectra:

IR: 1780; 1740; 1720

NMR: H6: 3.41-3.47; dd; J=3 & 8.5 Hz H5: 4.24-4.35; ddd; J=3, 8.5 & 10Hz

Step C

M⁺ =K⁺

Conditions: PPh₃ ; Pd(PPh₃)₄ ; ##STR246##

Yield: 63%

Spectra:

UV: 288

ε ext: 5345

EXAMPLE 2 Step A ##STR247##

Conditions: 1) 1 hr.; R.T.; Mg/THF 2) 0°; 15 min; THF; pyridylthioester

Yield: 76%

Spectra

IR: 1745; 1680; 1615

Step B

Conditions: Xylene; 136°-8°; 1.5 hrs.

Yield: 50%

Spectra

IR: 1780; 1740; 1718

NMR: H6: 3.42-3.48; dd; J=3 & 8 Hz H5: 4.25-4.36; ddd; J=3, 10 & 9 Hz

Step C

M⁺ =K⁺

Conditions: Pd(PPh₃)₄ ; PPh₃ ##STR248##

Yield: 42%

Spectra:

UV: 281

EXAMPLE 5 Step A ##STR249##

Conditions

1) BuLi/THF; -78°

2) MgBr₂ ; THF

3) 0°; 30 min; pyridylthioester

Yield: 57%

Spectra:

IR: 1745; 1685; 1650; 1620

Step B

Conditions: Xylene; 130°; 2.5 hrs.

Yield: 60%

Spectra:

IR: 1785; 1740; 1720

NMR: H6: 3.4-3.5; dd; J=3 & 8 Hz H5: 4.24-4.38; ddd; J=3, 9 & 10 Hz

Step C

Conditions: Pd(PPh₃)₄ ; PPh₃ ##STR250##

Spectra:

UV: 292

EXAMPLES 9, 11, 13 Step A ##STR251##

Conditions:

1) BuLi/THF; -78°

2) MgBr₂ ; THF

3) 0°; 30 min; pyridylthioester

Yield: 29%

Spectra:

IR: 1745; 1685; 1650: 1625

Step B

Step B1: Cyclization of ylide ketone to carbapenem

Step B2: Oxidation of sulfide to sulfoxide

Step B3: Oxidation of sulfide to sulfone

Conditions

B1: Xylene; 130°; 2 hrs.

Yield: 75%

Spectra:

IR: 1780; 1745; 1720

NMR: H6: 3.4-3.46; dd; J=3 & 8 Hz H5: 4.24-4.36; ddd; J=3, 9 & 10 Hz

Conditions

B2: mCPBA; 1.5 eq.; NaHCO₃ ; 0°; 1 hr. CH₂ Cl₂ ; workup with Na₂ S₂ O₃ ;purification on silica gel

Yield: 53% (sulfoxide)

Spectra:

IR: 1780; 1740; 1720

NMR: H6: 3.43-3.80; dd; J=3 & 8 Hz H5: 4.27-4.38; ddd; J=3, 9 & 10 Hz

Conditions:

B3: mCPBA; 2.5 eq.; NaHCO₃ ; 0°; 1 hr; CH₂ Cl₂

Yield: 74% (sulfone)

Spectra:

IR: 1780; 1740; 1720

NMR: H6: 3.46-3.52; dd; J=3 & 8 Hz H5: 4.3-4.41; ddd; J=3, 9 & 10 HzSCH₃ : 3.12(s)

Step C

M⁺ =Na⁺

Conditions: PPh₃ ; Pd(PPh₃)₄ ; ##STR252##

Yield: 17% of sulfide 9 from Step B1

Spectra:

UV: 295

ε ext: 2820

Yield: 62% of sulfoxide 11 from Step B2

Spectra:

UV: 295

ε ext: 7343

Yield: 73% of sulfone 13 from Step B3

Spectra:

UV: 296

ε ext: 7280

EXAMPLE 17 Step A ##STR253##

Conditions: 1) Mg/THF; 1 hr.; R.T. 2) 0°; 15 min; THF; pyridylthioester

Yield: 57%

Step B

Conditions: Xylene; 130°; 2 hrs.

Yield % 49%

Spectra

IR: 1780; 1740; 1720

NMR: H6: 3.42-3.47; dd; 3 & 8.5 Hz H5: 4.23-4.36; ddd; 3, 8.5 & 9.5 Hz

Step C

M⁺ =K⁺

Conditions: PPh₃ ; Pd(PPh₃)₄ : ##STR254##

Yield: 36%

UV: 300

ε ext 5365

EXAMPLES 35 & 37 Step A

Step A1: Preparation of ylide ketone

Step A2: Desilylation of silyl ether

Step A1 ##STR255##

Conditions:

1) Mg/THF; 3 hr./R.T.

2) 0°; 15 min; THF; pyridylthioester

Yield: 67%

Step A2

Conditions: CH₃ OH/H₂ SO₄ ; 0°; 1.25 hrs

Yield: 81%

Step B

Step B1: Cyclization of ylide ketone to carbapenem

Step B2: Oxidation of carbinol to aldehyde

Conditions

B1: Xylene; 130°; 1.5 hrs.

Yield: 83%

Conditions:

B2: Powdered 3 Å mol. sieves; N-methyl morpholine N-oxide;Tetra(n-propyl)ammonium perruthenate; methylene chloride; 15 mins; R.T;filter through silica gel and evaporate solvent.

Yield: 15%

Spectra:

IR: 1780; 1745; 1720

Step C

Step C1: Deallylation of carbinol to example 35

Step C2: Deallylation of aldehyde to example 37

M⁺ =K⁺

Conditions: PPh₃ ; Pd(PPh₃)₄ :

C1: ##STR256##

Yield: 36% of 35

Spectra:

UV: 302

ε ext 4030

Conditions: M⁺ =Na⁺

C2: PPh₃ ; Pd (PPh₃)₄ ##STR257##

Yield: 28% of 37

Spectra:

UV: 333

ε ext 2025

EXAMPLE 36 Step A ##STR258##

Conditions:

1) ˜1 hr; R.T.; Mg/THF

2) 0°; 15 min.; THF; pyridylthioester

Yield: 45%

Step B

Step B1: Formation of carbapenem from ylide ketone

Step B2: Desilylation of silylether to the carbinol

Conditions:

B1 Xylene; 136°-8°; ˜1.5 hrs.

Yield: 56%

Spectra:

IR: 1780; 1740; 1720

NMR: H6: 3.38-3.44; dd; J=3 & 8 Hz H5: 4.22-4.34; ddd; J=3,9 & 10 Hz

Conditions:

B2: n-Bu₄ NF; AcOH; THF; 3 hrs; 0°

Yield: 32%

Spectra

NMR: H6: 3.41-3.47; dd; J=3 & 8 Hz H5: 4.23-4.35; ddd; J=3, 9 & 10 Hz

Step C

M+=K+ ##STR259##

Conditions PPh₃ ; Pd(PPh₃)₄ ; ##STR260##

Yield: 27%

Spectra

UV: 300

EXAMPLE 60 Step A

Step A1: Preparation of ylide ketone

Step A2: Desilylation of silyl ether to carbinol ##STR261##

Conditions:

A1:

1) Mg/THF; 3 hrs.; R.T.

2) 0°; 15 min; pyridylthioester

Yield: 23% of ylide ketone

Spectra;

IR: 1740; 1690; 1645; 1620

A2: CH₃ OH; H₂ SO₄

Yield: 72% of carbinol

Spectra:

IR: 3100(OH); 1740; 1685; 1620

Step B

Conditions: Xylene; 130°; 3 hrs.

Yield 81%

Spectra:

IR: 3500(OH); 1740; 1720

NMR: OH: 1.96-2.06; t; J=6 Hz CH₂ O: 4.80-4.86; d; J=6 Hz H6: 3.40-3.49;dd; J=3 & 8 Hz H5: 4.24-4.38; ddd; J=3, 8.5 & 9.5 Hz

Step B

Conditions: PPh₃ ; Pd(PPH₃)₄ ; ##STR262##

Yield: 63%

Spectra:

UV: 296

ε ext: 5638

EXAMPLES 120, 122 & 124 Step A ##STR263##

Conditions:

1) BuLi/THF; -78°

2) MgBr₂ ; THF

3) 0°; 30 min; pyridylthioester

Yield: 69%

Step B

Step B1: Cyclization of ylide ketone to carbapenem

Step B2: Oxidation of sulfide to sulfoxide and sulfone

Conditions:

B1: Xylene; 130°; 2.5 hrs.

Yield: 94%

Spectra:

NMR: H6: 3.4-3.48; dd; J=3 & 8.5 Hz H5: 4.24-4.37; ddd; J=3, 9 & 10 HzSCH₃ : 2.53(s)

Conditions:

B2: mCPBA; NaHCO₃ ; CH₂ Cl₂ 0°; 1 hr; workup with Na₂ S₂ O₃ ;purification on silica gel

Yield: 49% (sulfoxide)

Spectra:

NMR: H6: 3.40-3.49; dd; J=3 & 8.5 Hz H5: 4.25-4.39 ddd; J=3, 9.5 & 10 HzSCH₃ : 2.96(s)

Yield: 28% (sulfone)

Spectra:

IR: 1780; 1745; 1725

NMR: H6: 3.43-3.51; dd; J=3 & 8.5 Hz H5: 4.26-4.40; ddd; J=3, 9 & 10 HzSCH₃ : 3.22(s)

Step C

M⁺ =Na⁺

Conditions: PPh₃ ; Pd(PPh₃)₄ : ##STR264##

Yield: 8% of sulfide (120) from Step B1

UV: 308

ε ext: 5584

Spectra:

Yield: 54% of sulfoxide (122) from Step B2

UV: 301

ε ext: 8301

Yield: 45% of sulfone (124) from Step B2

Spectra:

UV: 298

ε ext: 6006

EXAMPLES 181, 183 & 193 ##STR265## Step A Step A1: Preparation of theYlide Silylether Ketone

Conditions:

1) Method A: Mg (2.2 eq); ##STR266## (1.2 eq); THF; reflux; 3 hrs 2)Pyridylthioester; THF; 0°; 1.5 hrs

Yield: 53%

Spectra:

MS: m/z 901(MI); 262 (Ph₃ P)

IR(CH₂ Cl₂): 1740 (carbonyls); 1620 (ylid) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): selected absorbances δ 0.14 (s, Si(CH₃)₂);0.94 (s, t-butyl Si); 1.16 (d, J=6 Hz, CH₃ CHO--); 2.79 (dd, H₆); 4.90(s, CH₂ OSi--); 5.75-6.00 (m, two CH₂ CH═CH₂); 711-8.21 (all aromaticprotons)

Step A2: Desilylation of the Ylide Silylether Ketone to Ylide AlcoholKetone

A solution of the arylketone (from Step A1) (116 mg, mmol) was dissolvedin 0.2N HCl in 9:1 MeOH:H₂ O (5.4 ml) at 0° with stirring under N₂.After 1 h at 0°, the reaction mixture was added to 2.7 ml 1M K₂ HPO₄ ;1.6 ml 1M KH₂ PO₄, H₂ O and EA and shaken well. Upon phase separation,the aqueous phase was again extracted with EA, and the combined organiclayers were washed with brine, dried, filtered (MgSO₄) and concentratedin vacuo. Preparative TLC on 2-1000μ Si Gel GF plates (eluting with 50%EA/CH₂ Cl₂ and extracting with 10% MeOH/CH₂ Cl₂) provided the purifiedhydroxymethyl arylketone (82 mg, 80%).

MS m/z 787 (MI); 509 (MI--Ph₃ P═O); 262 (Ph₃ P) IR 2965 (CH₂ Cl₂): 3600(OH); 1740 (carbonyls); 1620 (ylid) cm⁻¹.

¹ H NMR (300 MHz, CDCl₃): δ selected absorbances 1.15 (d, J=6 Hz, CH₃CHO--); 2.78 (dd, J=2 & 10 Hz, H₆); 4.87 (s, CH₂ OH); 5.74-6.00 (m, twoCH₂ --CH═CH₂).

Step A3: Oxidation of Alcohol to Acid and Protection as Allylester

A solution of the hydroxymethyl arylketone from Step A2 (54 mg, 0.07 ml)in acetone (0.7 ml) with stirring at 0° was treated with Jones reagent,2.6M in CrO₃ (35 μl, 0.09 mmol). After 20 min., a second equivalentamount of Jones reagent was added, and stirring was continued for 15min. Upon removal of the cooling bath, stirring was continued for 30min., and then isopropanol (30 μl) was added. After 5 mins., Na₂ SO₄ wasadded, and the reaction mixture was stirred, then filtered, and theinsoluble residue washed well with CH₂ Cl₂. The filtrate wasconcentrated in vacuo and chased a few times with toluene to provide ayellow foam. The foam was chromatographed on a small column of Si Gelpacked and applied in CH₂ Cl₂ and then eluted with 0.5% HAc/CH₂ Cl₂. Thedesired fractions were concentrated in vacuo and chased repeatedly withtoluene to give the purified carboxylic acid (54 mg, 98% yield). Theacid was immediately dissolved in DMF (0.8 ml) and stirred with DIEA(17.3 μl, 0.1 mmol) and allyl bromide (8.6 μl, 0.1 mmol) under N₂. After1 h, an additional amount of DIEA (35 μl, 0.2 mmol) and allyl bromide(17 μl, 0.2 mml) was added, and the reaction mixture was stirred for anadditional few hours. The reaction mixture was concentrated in vacuo,and the residue was partitioned between ethyl acetate (EA), 1M K₂ HPO₄(1 ml) and 1M KH₂ PO₄ (1 ml) and then washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to provide crude product (46 mg).Preparative TLC on 2-1000μ Si Gel GF plates (eluting with 20% EA/CH₂ Cl₂and extracting with 10% MeOH/CH₂ Cl₂) provided the purified allylatedarylketone (35 mg, 63% yield).

R_(f) on Si gel analytical plates (eluant=0.5%

HAc/CH₂ Cl₂); R_(f) (acid)=0.3, (eluant=20%

EA/CH₂ Cl₂); R_(f) (allylester)=0.8.

Step B

Step B1: Cyclization of ylide silylether ketone from Step A1 to thecarbapenem

Step B2: Desilylation of carbapenem silylether

Step B3: Oxidation of carbinol to aldehyde

Step B4: Cyclization of diester from step A3 to Carbapenem

B1:

Conditions: Xylene; reflux; 1 hr

Yield: 80%

Spectra:

¹ H NMR (300 MHz, CDCl₃): δ 0.14 (s, Si(CH₃)₂); 0.95 (s, t-butyl-Si);1.49 (d, J=6 Hz, CH₃ CHO--); 3.22 (dd, J=10 & 18 Hz, H_(1a)); 3.32 (dd,J=8 & 18 Hz, H_(1b)); 3.42 (dd, J=3 & 8 Hz, H₆); 4.30 (m, H₅); 4.50-4.74(m, two CH₂ CH═CH₂); 4.88 (s, CH₂ OTBDMSi); 5.11-5.40 (m, two CH₂CH═CH₂); 5.76-601 (m, two CH₂ --CH═CH₂); 7.16-7.53 (m's, phenyl andthienyl protons).

B2:

To a solution of the cyclized material (12 mg, 0.02 mmol) in THF (0.6ml) with stirring at 0° under N₂, 1M Bu₄ NF in THF (80 μl, 0.08 mmol)and acetic acid (14 μl, 0.24 mmol) were added. The reaction mixture wasstirred for 1 hr at ambient temperature. Both EA and H₂ O were added tothe reaction mixture. After phase separation, the aqueous layer wasextracted again with EA. The combined organic layer was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo to provide thecrude product (11 mg). Preparative TLC on 1-1000μ Si Gel GF plate(eluting with 50% EA/hexane and extracting with 10% MeOH/CH₂ Cl₂)provided the purified hydroxymethyl carbapenem (3.5 mg, 35% yield).

IR(CH₂ Cl₂): 1780 (β-lactam); 1740 & 1715 (carbonate and ester) cm⁻¹.

¹ H NMR (300 MHz, CDCl₃): δ 1.49 (d, J=6 Hz, CH₃ CHO--); 1.85 (t, J=6Hz, OH); 3.13 (dd, J=10 and 18 Hz, H_(1a)); 3.32 (dd, J=9 & 18 Hz,H_(1b)); 3.43 (dd, J=3 & 8 Hz, H6); 4.59-4.74 (m's, two CH₂ CH═CH₂);4.88 (d, J=6 Hz, CH₂ OH); 5.13-5.40 (m, two CH₂ CH═CH₂); 5.76-6.01 (m,two CH₂ CH═CH₂); 7.24-7.55 (m's, phenyl and thienyl protons)

B3:

To a solution of the hydroxymethyl carbapenem from Step B2 (70 mg, 0.14mmol) in sieved CH₂ Cl₂ (1.8 ml) with stirring (drying tube),4-methylmorpholine-N-oxide (24 mg, 0.2 mmole) and 20 mg powdered 3 Åmolecular sieves (previously activated at 110°) were added. Stirring wascontinued for 10 min., after which tetrapropyl ammonium perruthenate(5.7 mg, 0.02 mmol) was added, and the reaction mixture was stirred for20 min at ambient temperature. The entire reaction mixture was thenfiltered through a column of 8 g Bakers Si Gel (60-200 mesh) packed inCH₂ Cl₂ and eluted with 10% EA/CH₂ Cl₂ to provide the purified formylcompound (54 mg, 77% yield) having an R_(f) =0.8 on Si gel in 20% EA/CH₂Cl₂. The R_(f) of the starting hydroxymethyl carbapenem in the samesystem was 0.4.

B4:

A solution of the tris-allylated arylketone (35 mg; 0.04 mmole) inxylene (3 ml) in the presence of a few crystals of hydroquinone washeated at reflux under N₂ for 1 hour. The reaction mixture wasconcentrated in vacuo without heat. The residue was purified bypreparative TLC on 1-500μ Si Gel GF plate (eluting with 10% EA/CH₂ Cl₂and extracting with 10% MeOH/CH₂ Cl₂) to give the tris allyl-protectedcarbapenem (5.4 mg, 23% yield).

R_(f) (10% EA/CH₂ Cl₂): 0.68.

IR (CH₂ Cl₂): 1780 (β-lactam); 1745 and 1715 (carbonate and estercarbonyls) cm⁻¹.

Step C:

Deblock of carbinol, aldehyde, and carboxylic acid

Conditions: Pd(Ph₃)₄ ; PPh₃ ##STR267##

Yield: 47% of carbinol 181

Spectra of 181:

UV (H₂ O): λmax=267 nm; λsh=305 nm (NH₂ OH quenchable)

ε: 8,000.

¹ H NMR (300 MHz, D₂ O): (no internal standard--DOH at 4.80); δ 1.28 (d,J=6 Hz, CH₃ CHO--); 3.02 (dd, J=10 & 18 Hz, H_(1a)); 3.39 (dd, J=8 & 18Hz, H_(1b)); 3.44 (dd, J=3 & 6 Hz, H₆); 4.15-4.26 (m, H₅ and CH₃ CHO);4.79 (s, CH₂ OH); 7.20-7.56 (m's, phenyl and thienyl protons)

Yield: 64% of aldehyde 193

Spectra of 193:

UV (H₂ O): λmax=260 nm; λsh=300 nm (NH₂ OH quenchable)

e: 11,000

¹ H NMR (300 MHz, D₂ O): (no internal standard--DOH at 4.80); δ1.27 (d,J=6 Hz, CH₃ CHO); 2.92 (dd, J=10 & 18 Hz, H_(1a)); 3.31 (dd, J=8 & 18Hz, H_(1b)); 3.42 (br dd, H₆); 4.21 (m, CH₃ CHO & H₅); 7.19-8.00 (phenyland thiophene protons); 9.63 (s, CHO)

Yield: 33% of potassium salt 183

For the preparation of 183, the general procedure of deallylation wasfollowed except for the addition of one more equivalent of potassium2-ethylhexanoate to aid the deblock of the third allyl group.

Spectra of 183:

¹ H NMR (300 MHz, D₂ O): (no internal standard--DOH at 4.80); δ1.29 (d,J=6 Hz, CH₃ CHO--); 3.11 (dd, J=10 & 18 Hz, H_(1a)); 3.47 (dd, J=8 & 18Hz, H_(1b)); 3.51 (m, H₆); 4.22-4.34 (m, CH₃ CHO & H₅); 7.28-7.86 (m's,phenyl and thiophene protons)

Examples Employing Stannane Chemistry

EXAMPLE 27 Sodium (1'R, 5R,6S)-6-(1'-hydroxyethyl)-2-[3"-hydroxymethyl-5"-(thien-2'"-yl)phenyl]carbapen-2-em-carboxylateSTARTING MATERIAL SYNTHESIS ##STR268##

To a solution of 2-(3',5'-dibromophenyl)thiophene (2.86 g, 9 mmol) inTHF (30 ml) with stirring at -78° under N₂, 1.6M BuLi (5.8 ml, 9.3 mmol)was added dropwise via an addition funnel. After a few mins. for theaddition and 5 min. additional stirring, DMF (0.9 ml, 11.6 mmol) wasadded, and the reaction was allowed to warm to ambient temperature.Stirring was continued for 3 h. The yellow solution was then poured intobrine (200 ml) and Et₂ O (100 ml), shaken, and separated. The aqueouslayer was again extracted with Et₂ O, and the combined organic layerswere washed with 1:1 brine/H₂ O (100 ml), dried (MgSO₄), filtered andconcentrated in vacuo to a yellow liquid with a tan precipitate. Hexane(a few ml) was added, and the residue was slurried and filtered. Theinsoluble portion was washed 2+ with hexane (few ml), and the soliddried in vacuo to give the diformylated material (496 mg, 19% yield).The hexane-soluble filtrate was re-concentrated in vacuo (2.38 g) andchromatographed on 60 g of Bakers Si gel (60-200 mesh) packed in hexane.The material was applied to the column in 1:2 CH₂ Cl₂ /hexane and elutedwith the same solvent system (300 ml) after which 10% Et₂ O in hexanewas used to elute the monoformyl material (814 mg). Approximately 630 mgof the material required further purification on 10-1000μ Si Gel GFplates (eluting and extracting with CH₂ Cl₂) to provide the purifiedmonoformylated compound (713 mg, 30% yield)

Data for 2-(3'-bromo-5'-formyl)phenylthiophene:

MS: m/z 266/268 (MI)

¹ H NMR (300 MHz, CDCl₃): δ 7.06 (dd, J=4 and 6 Hz, H.sub.β); 7.32 (dd,J=0.5 and 6 Hz, H.sub.α); 7.33 (dd, J=0.5 and 4 Hz, B.sub.β'); 7.82,7.90 and 7.96 (3 m's, 3 phenyl H's); 9.93 (s, CHO)

Data for 5-(3'-bromo-5'-formyl)phenyl-2-thiophenecarboxaldehyde:

MS: m/z 294/296 (MI)

¹ H NMR (300MHz, CDCl₃): δ 7.43 & 7.73 (2 d's, J=4 Hz, H.sub.β &H.sub.β'): 7.95, 7.97 and 8.01 (3 m's, 3 phenyl H's); 9.87 & 9.94 (2s's,2 CHO's).

2-(3'-BROMO-5'-HYDROXYMETHYL)PHENYLTHIOPHENE ##STR269##

To a solution of 2-(3'-bromo-5'-formyl)thiophene (707 mg, 2.7 mmol) inMeOH(26 ml) with stirring at 0° was added NaBH₄ (125 mg, 3.3 mmol), andafter some initial foaming, stirring was continued at 0° for 35 min. Thereaction mixture was concentrated to a small volume of yellow oil undera N₂ stream. Et₂ O (30 ml) and brine (30 ml) were added, and thereaction mixture was shaken in a separatory funnel. After phaseseparation, the aqueous layer was again extracted with ether. Thecombined organic layers were backwashed with brine, dried (MgSO₄),filtered and concentrated in vacuo to give the crude alcohol (735 mg) asan off-white solid. Preparative TLC of 304 mg of this substance on4-1000μ Si Gel GF plates (eluting with 5% EA/CH₂ Cl₂ and extracting with10% MeOH/CH₂ Cl₂) provided the purified hydroxymethyl compound (278 mg).

¹ H NMR (300 MHz, CDCl₃): δ 4.72 (s, CH₂ OH); 7.06 (m, H.sub.β ofthiophene); 7.30 (m, H.sub.α and H.sub.β' of thiophene); 7.42, 7.50 &7.66 (3 br m's, phenyl H's).

2-[3'-(TRIMETHYLTIN)-5'-(HYDROXYMETHYL)PHENYL]THIOPHENE ##STR270##

To a solution of the bromohydroxymethyl compound (274 mg, 1.0 mmol) intoluene (4 ml), tetrakistriphenylphosphine palladium (24 mg, 0.02 mmol)and triphenylphosphine (2.9 mg, 0.01 mmol) were added. A gentle streamof N₂ was blown through the reaction mixture followed by the addition ofhexamethylditin (459 mg, 1.4 mmol) in toluene (1 ml). The reactionmixture was covered with N₂ and refluxed for 2 h. By analytical TLC thereaction appeared to stop at a 50% conversion, so additionaltetrakistriphenylphosphine palladium (22 mg) was added, and heating wascontinued for another hour whereupon analytical TLC indicatedessentially 100% conversion to a less polar spot (5% EA/CH₂ Cl₂). Thereaction mixture was partitioned between EA/H₂ O and cold saturatedNaHCO₃. The organic layer was then washed 3× cold saturated NaHCO₃, 2×brine, dried (MgSO₄), filtered, and concentrated in vacuo to a yellowoil. Preparative TLC on 4-1000μ Si Gel GF plates (eluting with 5% EA/CH₂Cl₂ and extracting with CH₂ Cl₂) provided the purified trimethyltincompound (246 mg, 69% yield).

¹ H NMR (300 MHz, CDCl₃): δ 0.33 (m, (CH₃)₃ Sn); 1.72 (t, J=6 Hz, OH);4.73 (d, J=6 Hz, CH₂ OH); 7.10 (m, H.sub.β of thiophene), 7.30 (2-m's,H.sub.α and H.sub.β' of thiophene); 7.40, 7.55 & 7.63 (3-br m's, phenylH's).

STANNANE COUPLING TO PREPARE CARBAPENEMS ##STR271##

In a 2-neck 25 ml round-bottom flask, a solution of the β-keto esterpictured above (obtained as in Flow Sheet B2) (109 mg, 0.31 mmol) inanhydrous THF (1.5 ml) was purged with N₂. With stirring, the solutionwas cooled to -78°, and diisopropylamine (48 μl, 0.34 mmol) was addeddropwise via a syringe. After 10 minutes, triflic anhydride (57 μl, 0.32mmol) was added dropwise via syringe. After 15 min. triethylamine (47μl, 0.34 mmol) was added followed by trimethylsilyltriflate (66 μl, 0.34mmol), and stirring was continued for 20 min. A solution of thetrimethyltin compound (118 mg, 0.34 mmol) in N-methyl-3-pyrrolidinonefollowed by a mixture of tris (2,4,6-trimethoxyphenyl)phosphine (13.5mg, 0.025 mmol) and Pd₂ (DBA)₃ •CHCl₃ (7.6 mg; 0.007 mmol) were addedfollowed immediately by 1.5M ZnCl₂ in Et₂ O (227 μl, 0.34 mmol). The-78° bath was removed, and the reaction mixture was quickly brought toambient temperature in a luke-warm water bath. The burgundy-coloredsolution was stirred for 30 min. and then poured into Et₂ O (60 ml)/EA(15 ml)/H₂ O (11 ml). After shaking well and separation of phases, theorganic layer was washed 3× with 1:1 brine/H₂ O (15 ml), dried (MgSO₄and treated with 30 mg charcoal), filtered and concentrated in vacuo togive a pink foam, the crude product (238 mg). Chromatography on a smallcolumn of Bakers Si Gel (60-200 mesh), packed and applied in CH₂ Cl₂ andeluting with CH₂ Cl₂ (20 ml), 5% EA/CH₂ Cl₂ (100 ml), 10% EA/CH₂ Cl₂,etc. provided the purified carbapenem (106 mg, 58% yield).

MS: m/z 592 (MI); 434 (MI-β-lactam cleavage); 117 (CH₃ CHOTMS), 73 (TMS)

IR(CH₂ Cl₂): 1775 (β-lactam); 1722 (ester) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): δ 0.14 (s, TMS); 1.29 (d, J=6 Hz, CH₃ CHO-);1.76 (t, J=6 Hz, OH); 3.22 (dd, J=10 & 18 Hz, H_(1a)); 3.25 (dd, J=3 and6 Hz, H₆); 3.33 (dd, J=8 & 18 Hz, H_(1b)); 4.20-4.31 (m's, CH₃ CHO &H₅); 4.69 (d, J=6 Hz, CH₂ OH); 5.25 (midpt. of 2d, J=14 Hz, nonequivalent CO₂ CH₂ Ar); 7.04 (m, 4'"- H of thiophene); 7.27 (m,2-thiophene H's & 1-phenyl H); 7.41 and 8.07 (2 d's, J=9 Hz, ArpNO₂);7.46 & 7.54 (2-br s's phenyl H's).

DEBLOCK (HYDROLYSIS OF SILYL ETHER AND HYDROGENOLYSIS OFp-NITROBENZYLESTER) ##STR272##

A solution of the protected carbapenem (100 mg, 0.17 mmol) in THF (3.9ml), EtOH (3.9 ml) and H₂ O (3 ml) was treated with HOAc (3 μl, 0.05mmol). The clear, colorless solution was stirred under N₂ for 3 hrs. at35°. After cooling to ambient temperature, the desilylated reactionmixture was briefly stirred with NaHCO₃ (31 mg, 0.37 mmol). The reactionmixture was covered with N₂, 10% Pd/C (13 mg) was added, and thereaction mixture was placed under a H₂ -filled balloon and stirred for 1hr at ambient temperature. After filtering through a pad of celite andwashing the pad well with additional water, the yellow filtrate cloudedand solids precipitated. Upon transfer of this filtrate to centrifugetubes and extraction with EtOAc, phase separation was still difficultdue to emulsions. The aqueous layer was separated and lyophilized at 0°to provide 60 mg yellow lyophilizate. The 60 mg was treated with 12%MeCN/H₂ O (1.5 ml), stirred well, and then centrifuged, after which theyellow aqueous layer was purified by preparative TLC on 3-1000μ RPS-Fplates (eluting with 12% MeCN/H₂ O in the cold and extracting the mainUV active band with 4:1 MeCN/H₂ O 60 ml). The usual work-up of theplates and lyophilization provided the purified title compound (19 mg,28%).

UV(H₂ O): λmax=290 nm, ε=19,000

¹ H NMR (300 MHz, D₂ O): (no internal standard--DOH at 4.80) δ 1.27 (d,J=6 Hz, CH₃ CHOH--); 2.94 (dd, J=10 & 18 Hz, H_(1a)); 3.33 (dd, J=8 & 18Hz, H_(1b)); 3.43 (dd, J=3 & 6 Hz, H₆); 4.18-4.24 (m's, H₁, & H₅); 4.57(s, CH₂ OH); 7.11 (m, 4'"-thiophene H); 7.39-7.46 (m's, 2-thiophene H's& 3-phenyl H's).

EXAMPLE 29 Sodium (1'R.5R.6S)-6-(1'-hydroxyethyl)-2-(3"-formyl-5"-thien-2'"-yl)phenyl]-carbapen-2-emcarboxylate Starting Material Synthesis2-[3'-(Trimethyltin)-5'-(Formyl)Phenyl]Thiophene ##STR273##

A solution of 2-[3'-(trimethyltin)-5'-(hydroxymethyl)phenyl]thiophene(118 mg, 0.34 mmol) was re-oxidized in benzene (10 ml) in the presenceof MnO₂ (1 g, excess). The reaction mixture was stirred vigorously for24 hrs. The next day the reaction was filtered, and the insolublesrinsed repeatedly with CH₂ Cl₂. The combined filtrates were concentratedin vacuo, then redissolved in CH₂ Cl₂, dried (MgSO₄), filtered andconcentrated as above to give the crude product. Preparative TLC on2-1000μ Si Gel GF plates (eluting with 1:1 hexane: CH₂ Cl₂ andextracting with CH₂ Cl₂) provided the purified formyl compound (84 mg,71%).

IR (CH₂ Cl₂): 1695 (CHO)cm⁻¹ :

¹ H NMR (300 MHz, CDCl₃): 0.38 (m, (CH₃)₃ Sn); 7.11 (m, 4'"-thiopheneH); 7.35 & 7.39 (2-m's, 2-thiophene H's): 7.89, 7.94 & 8.00 (3-m's,3-phenyl H's); 10.04 (s, CHO).

Stannane Coupling ##STR274##

A solution of the β-ketoester (79 mg, 0.23 mmol) was treated asindicated in Example 27, Stannane Coupling, using a solution of theformyl compound (84 mg, 0.24 mmol) to provide upon work-up the crudecarbapenem (134 mg), a pink foam. Chromatography on a small column ofBakers Si Gel (60-200 mesh) packed and applied in CH₂ Cl₂ and elutedwith CH₂ Cl₂ until the pink band had emerged was followed by elutionwith 1% EtOAc/CH₂ Cl₂. The appropriate fractions were dried (MgSO₄) andconcentrated to provide the purified carbapenem (79 mg; 58%).

MS: m/z 590(MI); 432 (β-lactam cleavage); 117(CH₃ CHOTMS); 73 (TMS).

IR (CH₂ Cl₂): 1780 (β-lactam); 1725 (ester carbonyl); 1700 (formyl)cm⁻¹;

¹ H NMR (300 MHz, CDCl₃): δ 0.15 (s, TMS); 1.30 (d, J=6 Hz, CH₃ CHOTMS);3.27 (dd, J=10 & 18 Hz, H_(1a)); 3.30 (dd, J=3 & 6 Hz, H₆); 3.39 (dd,J=8 & 18 Hz, H_(1b)): 4.22-4.36 (m's, H_(1') & H₅); 5.27 (midpt. of 2d,J=14 Hz, non-eq. CO₂ CH₂ Ar); 7.09 (m, 4'"-thiophene H); 7.34 (m,2-thiophene H's); 7.46 & 8.09 (2d's, J=8 Hz, ArpNO₂); 7.72, 7.80 & 8.01(3-m's,3-phenyl H's); 10.00 (s, CHO).

Deblock ##STR275##

A solution of the carbapenem (77 mg, 0.13 mmol) was deblocked as was theanalogous hydroxymethyl carbapenem in Example 27, except that anincreased amount of catalyst, 10% Pd/C (22 mg) was used. After 30 minunder a balloon filled with H₂, another 22 mg of 10% Pd/C wasintroduced, and the hydrogenolysis was continued for 30 min more. Thesolution was transferred to a centrifuge test tube, and most of thecatalyst was centrifuged to the bottom. The supernatant was placed in aflask, and the catalyst was washed 4× with H₂ O (5 ml) filtering intothe original flask through a pad of celite. The clear filtrate wasconcentrated to a small volume with little or no heat in vacuo and thenlyophilized at 0° to give the crude product (69 mg). The crude materialwas applied in 1.2 ml H₂ O to 2-1000μ RPS-F plates eluting with 30% CH₃CN/H₂ O in the cold to give upon the usual work-up and lyophilization asample of the title compound (23 mg) which contained an impurity by 300MHz ¹ H-NMR. Further purification on 2-1000μ RPS-F plates eluting with15% CH₃ CN/H₂ O provided separation of the desired product from aforward running impurity, suspected to be the analogous carbapenamresulting from double bond reduction. The usual work-up of the platesand lyophilization provided the title compound (12 mg, 23% yield) freeof the impurity.

UV(H₂ O): λ_(max) =290 mμ, ε=8,900

¹ H-NMR (300 MHz, D₂ O): 1.32 (d, J=6 Hz, CH₃ CHOH--); 2.98 (dd, J=10 &16 Hz, H_(1a)); 3.34 (dd, J=8 & 16 Hz, H_(1b)); 3.48 (dd, J=3 & 6 Hz,H₆); 4.20-4.30 (m's H_(1') & H₅); 7.12 (m, 4'"-thiophene H); 7.38 & 7.44(2-m's, 2 thiophene H's); 7.58, 7.68 & 7.78 (3 br s's, phenyl H's); 9.70(s, formyl).

EXAMPLE 76 Sodium (1'R, 5R,6S)-6-(1'-hydroxyethyl)-2-[3"-hydroxymethyl-5"-(2'"-hydroxymethylthien-5'"-yl)-phenyl]-carbapen-2-em-carboxylateStarting Material Synthesis5-(3'-Bromo-5'-Hydroxymethyl)Phenyl-2-Hydroxymethylthiophene ##STR276##

A sample of 5-(3'-bromo-5'-formyl)phenyl-2-thiophenecarboxaldehyde fromExample 27, (223 mg, 0.76 mmol) was dissolved in MeOH (15 ml) and cooledto 0° with stirring. To the still partially heterogeneous reactionmixture NaBH₄ (73 mg, 1.9 mmol) was added. After 1 hour at 0° duringwhich time a homogeneous solution had resulted, the solution wasconcentrated under a N₂ stream. Partitioning between brine (20 ml)/Et₂ O(20 ml)/and EA (10 ml), the phases were separated, and the aqueous layeragain extracted with EA. The combined organic layers were washed withbrine, dried (MgSO₄), filtered, and concentrated in vacuo to give thecrude product. Preparative TLC on 4-1000μ Si Gel GF plates (applied inwarm acetone, eluted and extracted with 10% MeOH/CH₂ Cl₂) provided thepurified diol (161 mg, 71% yield).

¹ H NMR (300 MHz, d₆ DMSO); δ 4.52 (d, J=6 Hz, CH₂ OH); 4.63 (d, J=6 Hz,CH₂ OH); 5.40 (t, J=6 Hz, CH₂ OH); 5.65 (t, J=6 Hz, CH₂ OH); 6.96 & 7.43(2 d's, J=4 Hz, thiophene H's) 7.40, 7.52 & 7.68 (3 br s's, 3 phenylH's)

5-(5'-Hydroxymethyl-3'-Trimethyltin)Phenyl-2-Hydroxymethylthiophene##STR277##

The diol (161 mg, 0.54 mmol) was treated as the monohydroxymethylcompound had been treated in Example 27, using hexamethylditin (200 μl,0.9 mmol). After 1 hour at reflux, the reaction appeared by analyticalTLC to have progressed only very slightly. An additional 19 mg oftetrakistriphenylphosphine palladium was added, and refluxing wascontinued for 1 hour. More catalyst (26 mg) was added, and after anotherhour at reflux the conversion was fairly complete. Work-up as in Example27 provided the crude product (303 mg). Extensive preparative TLCchromatography eluting with 10% MeOH/CH₂ Cl₂, isolating, then elutingwith 50% EA/hexane, isolating, and then eluting with 5% MeOH/CH₂ Cl₂finally provided the purified trimethyltin compound (92 mg, 45% yield)

¹ H NMR (300 MHz, CDCl₃): δ 0.32 (m, (CH₃)₃ Sn); 1.68 (t, J=6 Hz, OH);1.79 (t, J=6 Hz, OH); 4.72 (d, J=6 Hz, CH₂ OH); 4.83 (d, J=6 Hz, CH₂OH); 6.97 & 7.18 (2 d's, J=4 Hz, thiophene H's); 7.40, 7.52 & 7.60 (3m's, 3 phenyl H's).

Stannane Coupling and Desilylation ##STR278##

A solution of the β-ketoester (75 mg, 0.22 mmol) was treated asindicated in Example 27, Stannane Coupling, using a solution of diol (90mg, 0.24 mmol) to provide upon work-up the crude carbapenem (104 mg).Since the crude material appeared to be partially desilylating on SiGel, it was immediately treated with THF (5.5 ml), EtOH (5.5 ml), H₂ O(4.2 ml), HOAc (4.2 μl) with stirring under N₂ at 35° for 1 hour to givethe more polar, desilylated carbapenem. The reaction mixture wasconcentrated a bit under N₂ and then stirred well with 1M K₂ HPO₄ (1ml), H₂ O and EA. After phase separation, the organic layer wasextracted with a combination of 1M K₂ HPO₄ (1 ml)/H₂ O/brine. Theorganic layer was dried (Na₂ SO₄) and concentrated in vacuo. PreparativeTLC (applied and eluted in 8% MeOH/CH₂ Cl₂ and extracted with 10%MeOH/CH₂ Cl₂) provided the purified desilylated carbapenem (68 mg, 64%yield) ready for hydrogenolysis.

Deblock ##STR279##

To a stirred solution of the desilylated carbapenem (68 mg, 0.12 mmol)in THF (2.9 ml), EtOH (2.9 ml) and H₂ O (2.2 ml) was added NaHCO₃ (14mg, 0.17 mmol) followed by 10% Pd/C (29 mg), and the reaction wascovered with a balloon of H₂ for 30 min. An additional 30 mg of catalystwas added, and the hydrogenolysis was continued as above for another hr.The usual work-up and lyophilization provided the crude product whichwas purified by preprative TLC on 2-1000μ RPS-F plates eluting in thecold with 15% CH₃ CN/H₂ O. The usual work-up of the plates andlyophilization provided the purified title compound (24 mg, 46% yield).

UV(H₂ O): λ_(max) =295 mμ; ε=20,000.

¹ H NMR (300 MHz, D₂ O):δ 1.26 (d, J=6 Hz, CH₃ CHOH--), 2.94 (dd, J=10 &17 Hz, H_(1a)); 3.31 (dd, J=8 & 17 Hz, H_(1b)); 3.42 (dd, J=2 & 3 Hz,H6); 4.2 (m, H_(1') & H₅); 4.54 & 4.72 (2 s's, 2 CH₂ OH's); 6.99 & 7.22(2 d's, J=4 Hz, thiophene H's); 7.14, 7.40 & 7.43 (3 br s's, phenylH's).

EXAMPLE 78 Sodium (1'R, 5R,6S)-6-(1'-hydroxyethyl)-2-[3"-formyl-5"-(2'"-formylthien-5'"-yl)phenyl]carbapen-2-em-carboxylateStarting Material Synthesis ##STR280##

The 5-(3'-bromo-5'-formyl)phenyl-2-thiophenecarboxaldehyde from Example27 (225 mg, 0.77 mmol) was stannylated as the hydroxymethyl compound hadbeen in Example 27. After 1.5 h at reflux, additional catalyst (21 mg)and a total of 485 mg hexamethylditin (1.5 mmol) was added. Afterrefluxing for an additional 2 hours, the conversion was judged completeby analytical TLC, and the reaction mixture was refrigerated overnight.Work-up as in Example 27 provided the crude product (340 mg).Preparative TLC on 4-1000μ Si Gel GF plates (eluting with 30% EA/Hexaneand extracting with 10% MeOH/CH₂ Cl₂) provided the purified trimethyltincompound (159 mg, 54% yield).

IR(CH₂ Cl₂): 1700 and 1670 (formyls) cm⁻¹

¹ H NMR (300 MHz, CDCl₃); δ 0.37 (m, (CH₃)₃ Sn); 7.03 & 7.30 (2 d's, J=4Hz, thiophene H's); 7.50 & 7.59 (2, m's, phenyl H's); 9.31 & 9.46 (2s's, 2 CHO's).

Stannane Coupling ##STR281##

A solution of the β-ketoester (133 mg 0.38 mmol) was treated asindicated in Example 27, Stannane Coupling, using a solution of thedialdehyde (155 mg, 0.41 mmol) to provide upon work-up the crudecarbapenem (221 mg). Chromatogaphy on a small column of Bakers Si Gel(60-200 mesh) eluting with CH₂ Cl₂ until the red band was halfway downthe column and then switching to 5% EA/CH₂ Cl₂ provided the purifiedcarbapenem (115 mg, 49%).

MS: m/z 618(MI) 460 (β-lactam cleavage), 117 (CH₃ CHOTMS), 73 (TMS)

IR(CH₂ Cl₂) 1780 (β-lactam), 1725 (ester), 1700 and 1670 (formyls) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): δ 0.16 (d, J=6 Hz, CH₃ CHOTMS); 3.27 (dd, J=10& 18 Hz, H_(1a)); 3.30 (dd, J=2.5 & 6 Hz, H₆); 3.40 (dd, J=9 & 18 Hz,H_(1b)); 4.24-4.38 (m's, H_(1') & H₅); 5.30 (midpt. of 2 d, J=14 Hz,non-equivalent CO₂ CH₂ Ar); 7.44 & 7.76 (2 d's, J=4 Hz, 2 thiopheneH's); 7.55 & 8.14 (2 d's, J=9 Hz, ArpNO₂); 7.85, 7.93 & 8.08 (3 m's, 3phenyl H's); 9.92 & 10.04 (2 s's, 2 CHO's).

Deblock: ##STR282##

A solution of the carbapenem (110 mg, 0.18 mmol) was deblocked as wasthe carbapenem in Example 27, Deblock. Upon work-up severe clogging ofthe celite pad resulted. The celite was washed with a THF/EtOH/H₂ Omixture, and all filtrates were concentrated in vacuo with little or noheat and then lyophilized at 0° to a yellow solid. Water (2 ml) wasadded to produce a slurry which was extracted 2× with EA (2 ml), and theaqueous layer was then purified by preparative TLC on 3-1000μ RPS-Fplates eluting with 10% MeCN/H₂ O in the cold. The usual work-up of theplates and lyophilization provided a low yield of the pure titlecompound (4 mg, 5%).

UV(H₂ O): λ_(max) =328 nm, ε=23,000

¹ H NMR (300 MHz, D₂ O): δ 1.35 (d, J=6 Hz, CH₃ CHOH--); 3.09 (dd, J=10& 16 Hz, H_(1a)); 3.44 (dd, J=8 & 16 Hz, H_(1b)); 3.54 (dd, J=3 & 6 Hz,H₆); 4.26-4.37 (m's, H_(1') & H₅); 7.49 & 7.90 (2 d's J=4 Hz, 2 thiopeneH's); 7.76, 7.79 and 7.90 (3 m's, 3 phenyl H's); 9.74 & 9.81 (2 s's,CHO's).

EXAMPLE 185 Sodium (1'R,5R,6S)-6-(1'-hydroxyethyl)-2-[(3"-carbamyl-5"-thien-2'"-yl)phenyl]carbapen-2-emcarboxyxlateStarting Material Synthesis 3-Bromo-5-(Thien-2'-Yl)Benzoic Acid##STR283##

To a solution of 2-(3'-bromo-5'-formyl)phenylthiophene (100 mg, 0.38mmol) from Example 27 in acetone (3.9 ml) with stirring at 0°, Jonesreagent (85 μl, 2.6M in CrO₃, 0.22 mmol) was added. After 30 min somealdehyde was still present by TLC. An additional 85 μl Jones reagent wasadded and stirring continued at 0° for 30 min. Isopropanol (73 μl) wasadded to quench any excess oxidant, and after 5 min at 0°, the reactionmixture was concentrated under a N₂ stream. The green residue waspartitioned between EA and H₂ O. The aqueous phase was again extractedwith EA, and the combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo. The residue was dissolvedin EA and H₂ O to which was added 5N NaOH (152 μl, 0.76 mmol), and thelayers were shaken well. The light brown aqueous layer was extracted 2×with EA and then layered with a third fresh quantity of EA. Afteraddition of 2N HCl (380 μl, 0.76 mmol) and vigorous shaking, the organiclayer was separated and the aqueous layer again extracted with EA. Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo to provide the purified carboxylic acid (84mg, 79%).

3-Bromo-5-(Thien-2'-Yl)Benzamide ##STR284##

To a solution of the carboxylic acid (84 mg, 0.3 mmol) in CH₃ CN (4.3ml) with stirring was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39mmol) and 1-hydroxy benzotriazole hydrate (78 mg, 0.58 mmol) dissolvedin THF (4.3 ml). The solution was stirred under N₂ for 20 min, and thena solution of 2.3M NH₃ in ethanol (3.4 ml, 7.8 mmol) was added causingthe previously clear reaction to turn cloudy. After stirring at roomtemperature for 20 min, the reaction was concentrated under a N₂ streamand then in vacuo. The residue was partitioned between EA and H₂ O,shaken well, the phases separated, and the aqueous was again extractedwith EA. The combined organic layers were washed with brine, dried(MgSO₄), filtered and concentrated in vacuo to give the crude amide (95mg) as a tan solid. The material was dissolved in THF andchromatographed on 2-1000μ Si Gel GF plates (eluting with 5% MeOH/CH₂Cl₂ and extracting with 10% MeOH/CH₂ Cl₂) to provide the purified amide(69 mg, 82% yield).

MS: m/z 281/283(MI).

¹ H-NMR (300 MHz, acetone-d₆): δ 6.85 (br abs, one NH of amide); 7.20,7.58 and 7.56 (3 m's, 3 thiophene H's); 7.76 (br abs, 2^(nd) NH ofamide); 8.00 & 8.20 (br m's, 3 phenyl H's).

3-(Trimethyltin)-5-(Thien-2'-YL)Benzamide ##STR285##

The benzamide (67 mg, 0.24 mmol) was treated as the analogoushydroxymethyl compound had been treated in Example 27. After 1 hour atreflux, a second batch of both the Pd° and phosphine catalysts wasadded, and refluxing was continued until conversion to the fasterrunning product was completed. Work-up as in Example 27 provided thecrude product (101 mg). This material was partially purified bypreparative TLC on 2-1000μ Si Gel GF plates (eluting and extracting with10% MeOH/CH₂ Cl₂). A second preparative TLC (eluting with 50% EA/hexaneand extracting with 50% EA/CH₂ Cl₂) provided the purified trimethyltincompound (59 mg, 67% yield).

MS: m/z 367(MI); 352(MI-CH₃)

IR(CH₂ Cl₂): 1680 (amide) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): δ 0.35 (m, (CH₃)₃ Sn); 6.05 & 6.20 (2 humps,CONH₂ 's); 7.09 (m, 4'"-thiophene H); 7.32 & 7.36 (2 m's, 2 thiopheneH's); 7.81, 7.83 and 7.95 (3 m's, 3 phenyl H's).

STANNANE COUPLING ##STR286##

A solution of the β-ketoester (53 mg, 0.15 mmol) was treated asindicated in Example 27, Stannane Coupling, using a solution of theamide (57 mg, 0.16 mmol), to provide upon work-up the crude carbapenem(88 mg). Chromatography on a small column of Bakers Si Gel (60-200 mesh)eluting with CH₂ Cl₂ (50 ml) then 20% EA/CH₂ Cl₂ provided the purifiedcarbapenem (57 mg, 63% yield).

IR(CH₂ Cl₂): 1780 (β-lactam), 1725 (ester), 1685 (amide) cm⁻¹

¹ H NMR (300 MHz, CDCl₃): δ 0.16 (s, TMS); 1.31 (d, J=6 Hz, CH₃CHOTMS--); 3.22-3.41 (3 dd, H_(1a), H_(1b) & H₆); 4.22-4.32 (m, H_(1') &H₅); 5.27 (midpt. of 2d's J=14 Hz, non-eq. CO₂ CH₂ Ar); 5.63 & 6.10 (2humps, CONH₂); 7.08 (m, 4'"-thiophene H); 7.33 (2 m's, 2 thiophene H's);7.46 & 8.10 (2d's, J=9 Hz, ArpNO₂); 7.49, 7.54 & 7.93 (3 m's, 3 phenylH's).

DEBLOCK ##STR287##

A solution of the carbapenem (55 mg, 0.09 mmol) was deblocked as was thecarbapenem in Example 29, Deblock. After the usual desilylation, 10%Pd/C (27 mg) was added, and the reaction mixture was stirred under aballoon of H₂ for 30 min. An additional 28 mg of 10% Pd/C was added andthe hydrogenolysis continued for an additional hour. After work-up asdescribed in Example 29, the lyophilizate was purified by preparativeTLC on 2-1000μ RPS-F plates eluting with 15% MeCH/H₂ O in the cold togive upon the usual work-up and lyophilization a sample of the titlecompound (21 mg) which contained a minor amount of what appeared to be adouble bond reduced analog by 300 MHz ¹ H NMR. The material wasre-prepped on 2-500μ RPS-F plates eluting with 7% MeCH/H₂ O, and the UVband was arbitrarily split in half. After the usual work-up andlyophilization, the slower half of the band (4.4 mg) was shown by ¹ HNMR to contain less of the impurity than the faster running half (7.5mg).

UV(H₂ O): λ_(max) =290 nm; ε=14,000

¹ H NMR (300 MHz, D₂ O): ε 1.28 (d, J=6 Hz, CH₃ CHOH--); 3.01 (dd, J=10& 16 Hz, H_(1a)); 3.38 (dd, J=8 and 16 Hz, H_(1b)); 3.47 (m, H₆); 4.24(m, H_(1') & H₅); 7.12, 7.38 & 7.42 (3 m's, 3 thiophene H's); 7.50, 7.66& 7.80 (3 br s's, 3 phenyl H's).

What is claimed is:
 1. A compound of the formula: ##STR288## wherein: Ris H or CH₃ ;R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;##STR289## is a 5- or 9-membered mono- or bicyclic heteroaryl ringsystem wherein 1 atom is O or S, or an 8-membered bicyclic heteroarylring system wherein 2 atoms are O and/or S; all the other atoms beingcarbon R^(a) is each independently selected from the group consisting ofhydrogen and the radicals set out below:a) a trifluoromethyl group:--CF₃ ; b) a halogen atom: --Br, --Cl, --F, or --I; c) C₁ -C₄ alkoxyradical: --OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substitutedby R^(q), where R^(q) is a member selected from the group consisting of--OH, --OCH₃, --CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (whereM^(a) is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (wherethe point of attachment is the carbon atom of the tetrazole ring and oneof the nitrogen atoms is mono-substituted by M^(a) as defined above) and--SO₃ M^(b) (where M^(b) is hydrogen or an alkali metal);d) a hydroxygroup: --OH; e) a carbonyloxy radical: --O(C═O)R^(s), where R^(s) is C₁-C₄ alkyl or phenyl, each of which is optionally mono-substituted byR^(q) as defined above or tri-substituted with --F;f) a carbamoyloxyradical: --O(C═O)N(R^(y))R^(z), where R^(y) and R^(z) are independentlyH, C₁₋₄ alkyl (optionally mono-substituted by R^(q) as defined above),together a 3- to 5-membered alkylidene radical to form a ring(optionally substituted with R^(q) as defined above) or together a 2- to4-membered alkylidene radical, interrupted by --O--, --S--, --S(O)--,--S(O)₂ -- or --NR^(e) --, to form a ring (where R^(e) is hydrogen, C₁-C₄ alkyl, and C₁ -C₄ alkyl mono-substituted with R^(q) and the ring isoptionally mono-substituted with Rq as defined above);g) a sulfurradical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) is defined above; h)a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above; i) azido: N₃ j) a formamido group: --N(R^(t))--C(O)H,where R^(t) is H or C₁ -C₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;k) a (C₁ -C₄alkyl)carbonylamino radical: --N(R^(t))--C(O)C₁₋₄ alkyl, where R^(t) isas defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; l) a (C₁ -C₄ alkoxy)carbonylamino radical: --N(R^(t))--C(O)OC₁ -C₄ alkyl, where R^(t) is asdefined above, and the alkyl group is also optionally mono-substitutedby R^(q) as defined above; m) a ureido group:--N(R^(t))--C(O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are asdefined above; n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s)and R^(t) are as defined above; o) a cyano group: --CN; p) a formyl oracetalized formyl radical: --C(O)H or --C(OCH₃)₂ H; q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂ C₁-C₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; r) carbonyl radical: --C(O)R^(s), where R^(s) is asdefined above; s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--C(R^(y))═NOR^(z) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; t) a (C₁ -C₄alkoxy)carbonyl radical: --C(O)OC₁₋₄ alkyl, where the alkyl isoptionally mono-substituted by R^(q) as defined above; u) a carbamoylradical: --C(O)N(R^(y))R^(z) where R^(y) and R^(z) are as defined above;v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring; w) athiocarbamoyl group: --C(S)N(R^(y))(R^(z)) where R^(y) and R^(z) are asdefined above; x) carboxyl: --COOM^(b), where M^(b) is as defined above;y) thiocyanate: --SCN; z) trifluoromethylthio: --SCF₃ ; aa) tetrazolyl,where the point of attachment is the carbon atom of the tetrazole ringand one of the nitrogen atoms is mono-substituted by hydrogen, an alkalimetal or a C₁ -C₄ alkyl optionally substituted by R^(q) as definedabove; ab) an anionic function selected from the group consisting of:phosphono [P=O(OM^(b))₂ ]; alkylphosphono {P=O(OM^(b))--[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P=O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P=O(OM^(b))N(R^(y))R^(z) and P=O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S in the case of a5-membered ring, and in which from 1 to 2 additional carbon atoms areoptionally replaced by a nitrogen heteroatom, and where the phenyl andheteroaryl are optionally mono-substituted by R^(q), as defined above;M^(b) is as defined above; and R^(y) and R^(z) are as defined above;ac)C₅ -C₇ cycloalkyl group in which one of the carbon atoms in the ring isreplaced by a heteroatom selected from O, S, NH or N(C₁ -C₄ alkyl) andin which one additional carbon atom may be replaced by NH or N(C₁ -C₄alkyl), and in which at least one carbon atom adjacent to each nitrogenheteroatom has both of its attached hydrogen atoms replaced by oneoxygen thus forming a carbonyl moiety and there are one or two carbonylmoieties present in the ring; ad) C₂ -C₄ alkenyl radical, optionallymonosubstituted by one of the substituents a) to ac) above and phenylwhich is optionally substituted by R^(q) as defined above; ae) C₂ -C₄alkynyl radical, optionally monosubstituted by one of the substituentsa) to ac) above; af) C₁ -C₄ alkyl radical; ag) C₁ -C₄ alkylmono-substituted by one of the substituents a)-ac) above; ah) a2-oxazolidinonyl moiety in which the point of attachment is the nitrogenatom of the oxazolidinone ring, the ring oxygen atom is optionallyreplaced by a heteroatom selected from -S- and NR^(t) (where R^(t) is asdefined above) and one of the saturated carbon atoms of theoxazolidinone ring is optionally mono-substituted by one of thesubstituents a) to ag) above; and M is selected from:i) hydrogen; ii) apharmaceutically acceptable esterifying group or removable carboxylprotecting group; or iii) an alkali metal or other pharmaceuticallyacceptable cation.
 2. A compound of claim 1 wherein R¹ is hydrogen.
 3. Acompound of claim 1 wherein R¹ is hydrogen and R² is (R)--CH₃ CH(OH)--or (R)--CH₃ CH(F)--.
 4. A compound of claim 3 wherein each R^(a) isindependently selected from:

    ______________________________________                                        --OCH.sub.3       --OCH.sub.2 CO.sub.2 CH.sub.3                               --OCH.sub.2 CH.sub.2 OH                                                                         --CF.sub.3                                                  --F               --Cl                                                        --Br              --I                                                         --OH              --OCOCH.sub.3                                               --OCONH.sub.2     --SCH.sub.3                                                 --SOCH.sub.3      --SO.sub.2 CH.sub.3                                         --SCH.sub.2 CH.sub.2 OH                                                                         --SOCH.sub.2 CH.sub.2 OH                                    --SO.sub.2 NH.sub.2                                                                             --SO.sub.2 N(CH.sub.3).sub.2                                --NHCHO           --NHCOCH.sub.3                                              --NHCO.sub.2 CH.sub.3                                                                           --NHSO.sub.2 CH.sub.3                                       --CN              --CHO                                                       --COCH.sub.3      --COCH.sub.2 OH                                             --CH═NOH      --CH═NOCH.sub.3                                         --CH═NOCH.sub.2 CO.sub.2 CH.sub.3                                                           --CH═NOCMe.sub.2 CONH.sub.2                             --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                                 --CO.sub.2 CH.sub.2 CH.sub.2 OH                             --CH═NOCMe.sub.2 CO.sub.2 Me                                                                --CONHCH.sub.3                                              --CONH.sub.2      --CONHCH.sub.2 CN                                           --CON(CH.sub.3).sub.2                                                                           --CONHCH.sub.2 CO.sub.2 CH.sub.3                            --CONHCH.sub.2 CONH.sub.2                                                                       --CONHCH.sub.3                                              --CONHOH          --CO.sub.2 CH.sub.3                                         --tetrazolyl      --CONHSO.sub.2 NH.sub.2                                     --SCF.sub.3       --SO.sub.2 NHCN                                             --CONHSO.sub.2 NH.sub.2                                                                         --CH═CHCN                                               --SO.sub.2 CF.sub.3                                                                             --CH═CHCO.sub.2 CH.sub.3                                --SO.sub.2 NHCONH.sub.2                                                                         --C.tbd.C--CN                                               --CH═CHCONH.sub.2                                                                           --CH.sub.2 N.sub.3 and                                      --C.tbd.C--CONH.sub.2                                                                           --CH.sub.2 I.                                               --CH.sub.2 OH                                                                 --CH.sub.2 CO.sub.2 CH.sub.3                                                  ______________________________________                                    


5. A compound of claim 3 wherein two R^(a) substituents are not H.
 6. Acompound of claim 1 of the formula ##STR290## wherein R² substituentscontaining a chiral center have the (R) configuration; and wherein thesubstituents are:

    __________________________________________________________________________    No.                                                                              R   R.sup.2 M R.sup.a                                                                             HARR.sub.2.sup.a                                       __________________________________________________________________________    1  H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR291##                                            2  H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR292##                                            3  H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR293##                                            4  H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR294##                                            5  H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR295##                                            6  H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR296##                                            7  H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR297##                                            8  H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR298##                                            9  H   CH(OH)CH.sub.3                                                                        Na                                                                              SMe                                                                                  ##STR299##                                            10 H   CH(OH)CH.sub.3                                                                        Na                                                                              SMe                                                                                  ##STR300##                                            11 H   CH(OH)CH.sub.3                                                                        Na                                                                              S(O)Me                                                                               ##STR301##                                            12 H   CH(OH)CH.sub.3                                                                        Na                                                                              S(O)Me                                                                               ##STR302##                                            13 H   CH(OH)CH.sub.3                                                                        Na                                                                              SO.sub.2 Me                                                                          ##STR303##                                            14 H   CH(OH)CH.sub.3                                                                        Na                                                                              SO.sub.2 Me                                                                          ##STR304##                                            15 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR305##                                            16 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR306##                                            17 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR307##                                            18 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR308##                                            19 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR309##                                            20 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR310##                                            21 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR311##                                            22 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR312##                                            23 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR313##                                            24 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR314##                                            25 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR315##                                            26 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR316##                                            27 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR317##                                            28 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR318##                                            29 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR319##                                            30 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR320##                                            31 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHNOH                                                                                ##STR321##                                            32 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHNOH                                                                                ##STR322##                                            33 H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR323##                                            34 H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR324##                                            35 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR325##                                            36 H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR326##                                            37 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR327##                                            38 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR328##                                            39 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR329##                                            40 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR330##                                            41 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR331##                                            42 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR332##                                            43 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR333##                                            44 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR334##                                            45 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR335##                                            46 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR336##                                            47 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR337##                                            48 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR338##                                            49 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR339##                                            50 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR340##                                            51 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR341##                                            52 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR342##                                            53 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR343##                                            54 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR344##                                            55 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR345##                                            56 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR346##                                            57 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR347##                                            58 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR348##                                            59 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR349##                                            60 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR350##                                            61 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR351##                                            62 H    CH(OH)CH.sub.3                                                                       Na                                                                              Br                                                                                   ##STR352##                                            63 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR353##                                            64 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR354##                                            65 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR355##                                            66 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR356##                                            67 H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR357##                                            68 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR358##                                            69 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR359##                                            70 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR360##                                            71 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR361##                                            72 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR362##                                            73 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR363##                                            74 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR364##                                            75 H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR365##                                            76 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR366##                                            77 H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR367##                                            78 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR368##                                            79 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR369##                                            80 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR370##                                            81 H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR371##                                            82 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR372##                                            83 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR373##                                            84 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR374##                                            85 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR375##                                            86 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR376##                                            87 H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR377##                                            88 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR378##                                            89 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR379##                                            90 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR380##                                            91 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR381##                                            92 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR382##                                            93 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR383##                                            94 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR384##                                            95 H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR385##                                            96 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR386##                                            97 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR387##                                            98 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR388##                                            99 H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR389##                                            100                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR390##                                            101                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR391##                                            102                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR392##                                            103                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR393##                                            104                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR394##                                            105                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR395##                                            106                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR396##                                            107                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR397##                                            108                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR398##                                            109                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR399##                                            110                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR400##                                            111                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR401##                                            112                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR402##                                            113                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR403##                                            114                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR404##                                            115                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR405##                                            116                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR406##                                            117                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR407##                                            118                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR408##                                            119                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR409##                                            120                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR410##                                            121                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR411##                                            122                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR412##                                            123                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR413##                                            124                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR414##                                            125                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR415##                                            126                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR416##                                            127                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR417##                                            128                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR418##                                            129                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR419##                                            130                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR420##                                            131                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              F                                                                                    ##STR421##                                            132                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR422##                                            133                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR423##                                            134                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR424##                                            135                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR425##                                            136                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR426##                                            137                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Cl                                                                                   ##STR427##                                            138                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR428##                                            139                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR429##                                            140                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR430##                                            141                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR431##                                            142                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR432##                                            143                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR433##                                            144                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR434##                                            145                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR435##                                            146                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR436##                                            147                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR437##                                            148                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR438##                                            149                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              I                                                                                    ##STR439##                                            150                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR440##                                            151                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR441##                                            152                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR442##                                            153                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR443##                                            154                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR444##                                            155                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR445##                                            156                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR446##                                            157                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR447##                                            158                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR448##                                            159                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR449##                                            160                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR450##                                            161                                                                              CH.sub.3                                                                          CH(OH)CH.sub.3                                                                        Na                                                                              Br                                                                                   ##STR451##                                            162                                                                              H   CH(F)CH.sub.3                                                                         Na                                                                              H                                                                                    ##STR452##                                            163                                                                              H   CH(F)CH.sub.3                                                                         Na                                                                              H                                                                                    ##STR453##                                            164                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR454##                                            165                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR455##                                            166                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR456##                                            167                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR457##                                            168                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR458##                                            169                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR459##                                            170                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR460##                                            171                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR461##                                            172                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR462##                                            173                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR463##                                            174                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR464##                                            175                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR465##                                            176                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR466##                                            177                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR467##                                            178                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR468##                                            179                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR469##                                            180                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CN                                                                                   ##STR470##                                            181                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR471##                                            182                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR472##                                            183                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR473##                                            184                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR474##                                            185                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR475##                                                                          ##STR476##                                            186                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR477##                                                                          ##STR478##                                            187                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR479##                                            188                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR480##                                            189                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR481##                                            190                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR482##                                            191                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR483##                                                                          ##STR484##                                            192                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                               ##STR485##                                                                          ##STR486##                                            193                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR487##                                            194                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              H                                                                                    ##STR488##                                            195                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR489##                                            196                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CH.sub.2 OH                                                                          ##STR490##                                            197                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR491##                                            198                                                                              H   CH(OH)CH.sub.3                                                                        Na                                                                              CHO                                                                                  ##STR492##                                            199                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR493##                                            200                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR494##                                            201                                                                              H   CH(OH)CH.sub.3                                                                        K H                                                                                    ##STR495##                                            __________________________________________________________________________


7. A pharmaceutical composition effective against bacteria comprising aneffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier therefor.
 8. A method for treating bacterialinfection in mammals comprising administering a pharmaceuticalcomposition comprising an effective amount of a compound of claim 1 anda pharmaceutically acceptable carrier therefor.
 9. A compositionaccording to claim 7 which further comprises an inhibitorily effectiveamount of a DHP inhibitor.
 10. A composition according to claim 9wherein said DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.
 11. A method according to claim 8 which further comprisesadministering an inhibitorily effective amount of a DHP inhibitor.
 12. Amethod according to claim 11 wherein said DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.
 13. A compound of claim 1 selected from the group consisting of:##STR496##